Stereoselective synthesis of isoquinuclidines through an Aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes

Article abstract of DOI:10.1021/ol500390a

A highly stereoselective aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes with N-sulfonyl aldimines is described. While this Lewis acid promoted heterocycloaddition provides an efficient strategy for constructing optically enriched isoquinuclidines, it is mechanistically intriguing. The cycloaddition favored the endo-II pathway in the absence of a viable bidentate coordination. This represents an unexpected switch from the anticipated endo-I selectivity obtained in the all-carbon cycloaddition.

Full text of DOI:10.1021/ol500390a

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Isoquinuclidines through an Aza-[4 + 2]
Cycloaddition of Chiral Cyclic 2‑Amidodienes
Li-Chao Fang and Richard P. Hsung*
Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States
S
* Supporting Information
ABSTRACT: A highly stereoselective aza-[4 + 2] cycloaddition of
chiral cyclic 2-amidodienes with N-sulfonyl aldimines is described.
While this Lewis acid promoted heterocycloaddition provides an
efficient strategy for constructing optically enriched isoquinucli-
dines, it is mechanistically intriguing. The cycloaddition favored the
endo-II pathway in the absence of a viable bidentate coordination.
This represents an unexpected switch from the anticipated endo-I
selectivity obtained in the all-carbon cycloaddition.
he isoquinuclidine [or 2-azabicyclo[2.2.2]octane] core is a
prevalent motif among biologically active natural prod-
Scheme 1. Cyclic 2-Amidodienes in [4 + 2] Cycloadditions
T
ucts.1 Catharanthine, an iboga-alkaloid, is a biosynthetic
precursor of dimeric vinca alkaloids such as vinblastin and
vincristine, which are being used as antitumor agents for
treatment of a number of human cancers (Figure 1).2
Figure 1. Bioactive natural products with isoquinuclidine core.
Moreover, Daphniphyllum alkaloids such as caldaphnidine D
have shown a variety of pharmacological activities such as
cytotoxicity and antioxidative activity.3 Xestocyclamine A, a
polycyclic alkaloid isolated from a marine sponge, exhibits
potent inhibitory property of PKCβ (PKC = protein kinase
C).4 Given such potential significance in cancer therapeutic
development, designing efficient methods to access the
isoquinuclidine core represents an important endeavor not
only for constructing these natural products but also advancing
biological studies that can lead to possible drug discovery.2−4
Recently, we5 reported a highly regio- and stereoselective
Diels−Alder cycloaddition featuring de novo chiral cyclic 2-
amidodienes 1 (Scheme 1) derived from allenamides.6 This
cycloaddition provides a facial entry to optically enriched
[2.2.2]bicyclic manifolds [1→2 in Scheme 1]. Despite a rich
history of amino and amido dienes,7,8 cyclic 2-amidodienes are
rare,9 and there certainly is a lack of overall systematic
exploration of their reactivities.10 Given the significance of
isoquinuclidine, we envisioned that an aza-[4 + 2] cyclo-
addition11,12 employing imines as heterodienophiles could
prove to be an efficient strategy for stereoselective con-
structions of optically enriched isoquinuclidines that have
mostly been synthesized through [4 + 2] cycloadditions of 1,2-
dihyropyridines.13−17 We wish to report here our success in
developing a highly stereoselective aza-[4 + 2] cycloaddition of
cyclic 2-amidodienes with N-sulfonyl aldimines and finding of
an unexpected switch in the selectivity.
We commenced our investigation by screening Lewis acid
conditions using cyclic 2-amidodiene 118 with N-Ts aldimine 4
serving as the dienophile. As shown in Table 1, although
aluminum- and boron-based Lewis acids were less effective
(entries 1−3) and TMSOTf is only marginal (entry 4), the best
promoter for this reaction appeared to be SnCl4, leading to the
desired cycloadduct 519 in 60% yield (entry 5). There are three
isomers found in this reaction with the major isomer being the
endo-II product (5b) and the two minor isomers being exo-I
and exo-II products 5c and 5d, respectively. The actual
stereochemical assignments were made using another cyclo-
Received: March 4, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
minor isomers of cycloadducts 9 were cleanly isolated as a
mixture and could be concisely assigned as a pair of exo-
cycloadducts, more specifically 9c and 9d, after its hydrolysis.21
(2) The tert-butyl-substituted imine was unfortunately not
tolerated likely due to the steric hindrance of the t-Bu group,
and aryl aldimines appear to be inferior substrates in terms of
selectivity (see 13). (3) With respect to nitrogen substitutions,
methane sulfonyl and Ns groups were not ideal (see 14 and 15,
respectively). In contrast, Ts- and PMP-sulfonyl groups were
very effective (see 16 and 17). (4) Lastly and most importantly,
the single-crystal X-ray structure the major isomer of
cycloadducts 12 reveals that it is 12b, therefore unambiguously
confirming the endo-II selectivity (Figure 2). Cycloadditions of
Table 1. Identifying of a Suitable Lewis Acid
a
temp
time
(h)
yield
(%)
b
entry
LA
solvent
(°C)
dr ratio
c
1
2
3
4
5
6
7
EtAlCl2
AlCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
−78
−78
−78
−78
−78
−78
rt
12
12
12
12
12
12
14
14
N.D.
38
33
48
60
52
no
60:(20:20)
N.D.
BF3−OEt2
TMSOTf
SnCl4
34:(33:33)
68:(16:16)
68:(16:16)
TiCl4
MgBr2
d
rxn
8
Zn(OTf)2
Yb(OTf)3
La(OTf)3
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
18
15
15
no rxn
no rxn
no rxn
9
10
Figure 2. X-ray structure of endo-II cycloadduct 12b.
a
b
Isolated yields; in all cases, 1.0 equiv of Lewis acid was used. Ratios
denote endo:exo with exo-I:exo-II ratios shown in parentheses. All ratios
c
determined using 1H and/or 13C NMR. N.D. = not determined.
other chiral cyclic 2-amidodienes with N-sulfonyl aliphatic
aldimines were also examined (Table 3). Depending on the
imine, in general, good selectivities as well as yields were
d
Complete recovery of the starting diene 1.
adduct. While TiCl4 afforded comparable diastereoselectivity
but gave a lower yield (entry 6), MgBr2 and Zn(OTf)2 were
ineffective in promoting the cycloaddition (entries 7 and 8).
Neither were rare earth metal triflates such as Yb(OTf)3 and
La(OTf)3 useful in this context (entries 9 and 10), although
they have been successfully utilized in aza-[4 + 2] reactions.20
Having identified a suitable Lewis acid, a series of N-Ts-
aldimines were examined as summarized in Table 2: (1) The
Table 3. Cycloadditions of Other Cyclic 2-Amidodienes
Table 2. Examining the Scope of aza-Dienophiles
a
Reaction conditions followed those described for entry 5 in Table 1.
b
All are isolated yields. Ratios denote endo:exo [a/b:c/d] with the exo-
a
I:exo-II ratio [c:d] shown in parentheses. They are determined using
Reaction conditions followed those described for entry 5 in Table 1.
c
d
b
1H and/or 13C NMR. PMP = p-methoxyphenyl. Stereochemistry of
All are isolated yields. Ratios denote endo:exo [a/b:c/d] with the exo-
e
I:exo-II ratio [c:d] shown in parentheses. They are determined using
each isomer was not unambiguously assigned. This ratio implies a
c
d
1H and/or 13C NMR. PMP = p-methoxyphenyl. This ratio implies a
f
single isomer is observed here. Only one exo-cycloadduct was seen but
g
e
unassigned whether it is exo-I or exo-II. Decomposition of starting
single isomer is observed here. Only one exo-cycloadduct was seen
diene 1 with no observable desired cycloadduct.
but unassigned whether it is exo-I or exo-II.
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Organic Letters
Letter
obtained including the usage of Sibi’s auxiliary (see diene 8).22
These results demonstrate that this cycloaddition can be useful
for constructing optically enriched isoquinuclidines.
the more stable 1-amidodienes.18 With some trepidation, we
carefully carried out cycloadditions of diene 6 with two enones
at high temperature as shown in Scheme 4. Although yields
Mechanistically, we became intrigued because the stereo-
chemical outcome is opposite from what we had anticipated. As
shown in Scheme 2, there are two possible low energy
Scheme 4. Reversal to the Endo-II Selectivity
Scheme 2. Two Rotameric Conformations of the Diene
rotameric conformations for these cyclic 2-amidodienes, syn
and anti, which can be defined by the position of the carbamate
carbonyl relative to the blue-colored olefin with respect to the
red C−N bond (see wavy arrows in Scheme 2). In both
rotamers, the nitrogen lone pair is coplanar and fully
delocalized into the diene motif. In our previous all-carbon
cycloaddition,5 the observed endo-I selectivity suggests that the
syn rotamer is operative because its substituent on the chiral
auxiliary shields the top endo-II face. Although Spartan B3LYP/
6-31G* calculations reveal that the anti rotamer is more
favored, the energetic difference is sufficiently small (i.e., ΔE =
−0.28 kcal mol−1 for diene 8) that it should not preclude the
possibility of the syn rotamer being the more reactive
conformer.
were not particularly high, we managed to isolate the desired
cycloadducts 34a/b and 35a/b with complete reversal of
selectivity from those obtained under Lewis acid conditions.
These results provide rather strong support for our assertion
that the cycloaddition prefers the energetically more favored
TS-endo-II (0.28 kcal mol−1 for diene 6)23 through the anti
rotamer and that, in the presence of a viable bidentate
coordination,24 this selectivity can be altered and/or completely
reversed.
In summary, we have developed a highly stereoselective aza-
[4 + 2] cycloaddition of 2-amidodienes and N-sulfonyl
aldimines. This Lewis acid promoted heterocycloaddition
provides an efficient strategy for constructing optically enriched
isoquinuclidines. Mechanistically, we uncovered an unexpected
switch from the anticipated endo-I selectivity. In the absence of
a chelation-dictated transition state, these aza-[4 + 2]
cycloadditions favored the endo-II pathway through the anti
rotamer. Further mechanistic study through calculation and its
applications in total synthesis of relevant alkaloids are currently
underway.
Consequently, we expected endo-I selectivity also for the
current aza-[4 + 2] cycloadditions, but instead, these are endo-II
selective processes, thereby implying a facial preference switch
with the anti rotamer being operative. Furthermore, as shown
in Scheme 3, Spartan B3LYP/6-31G* calculations demonstrate
Scheme 3. Unexpected Switch in the Facial Preference
ASSOCIATED CONTENT
* Supporting Information
■
S
that TS-endo-II is actually lower in energy than TS-endo-I (1.41
kcal mol−1 for diene 1).23 This energetic different in the
transition states agrees quite well with our observed stereo-
chemical outcome. To reconcile these differences, we suspect
that the previous cycloaddition involved a highly organized
transition-state through a long distance chelation with the tin
metal coordinating to both carbonyl oxygen atoms (right-hand
side in Scheme 3). This bidentate coordination is likely only
feasible with TS-endo-I (d = 5.1 Å) given the much longer
distance between the same two oxygen atoms in TS-endo-II (d
= 6.0 Å, not shown).
Experimental procedures as well as NMR spectra, character-
izations, and X-ray structural files. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rhsung@wisc.edu.
Notes
The authors declare no competing financial interest.
To provide support for this proposal, we examined the all-
carbon cycloaddition in the absence of any Lewis acids. We had
previously avoided this condition because these cyclic 2-
amidodienes tend to undergo isomerization via a 1,5-H shift at
high temperatures over an extended period of time, leading to
ACKNOWLEDGMENTS
■
We thank the NIH (GM0-66055) for financial support and Dr.
Victor Young at the University of Minnesota for X-ray
structural analysis.
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Letter
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(g) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 190, 1.
(h) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
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