Strain-Release Driven Cycloadditions for Rapid Construction of Functionalized Pyridines and Amino Alcohols

Article abstract of DOI:10.1021/acs.orglett.9b01652

This paper describes the development of a new variant of stereoselective strain-release driven reactions (formal homo [3 + 2] dipolar cycloadditions) which utilize housane (1) to construct functionalized amino alcohols and pyridine-substituted cyclopentanes in two to three steps from simple and easily available building blocks (nitrones and pyridine N-oxides respectively).

Full text of DOI:10.1021/acs.orglett.9b01652

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Strain-Release Driven Cycloadditions for Rapid Construction of
Functionalized Pyridines and Amino Alcohols
Sebastian Clementson,†,§ Alessio Radaelli,†,‡,§ Kasper Fjelbye,† David Tanner,*,‡ and Mikkel Jessing*,†
†Molecular Discovery and Innovation, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
‡Department of Chemistry, Technical University of Denmark, 207 Kemitorvet, 2900 Kgs. Lyngby, Denmark
S
* Supporting Information
ABSTRACT: This paper describes the development of a new
variant of stereoselective strain-release driven reactions (formal
homo [3 + 2] dipolar cycloadditions) which utilize housane (1) to
construct functionalized amino alcohols and pyridine-substituted
cyclopentanes in two to three steps from simple and easily avail-
able building blocks (nitrones and pyridine N-oxides respectively).
elief of ring strain1−3 is a powerful tactic to enable
efficient access to complex molecular scaffolds which
R
would otherwise be difficult to synthesize.4−7 Recently, the
bench-stable strain-release reagent “housane” (1), which is
now commercially available, was introduced for the synthesis
of a wide range of 1,3-disubstituted cyclopentanes via an SN2′-
type reaction.8 Bicyclic sulfone 1 can be prepared in 99.5%
enantiopurity, and the reaction proceeds with complete
stereochemical control at the new C−Nu bond (Figure 1A).
In connection with a medicinal chemistry synthesis program,
we considered the prospect of reacting 1,3-dipoles with 1 in
order to form 1,3-difunctionalized cyclopentane moieties by
intramolecular trapping of the presumed sulfone-stabilized
anionic intermediate (Figure 1B). For exploratory studies of
this formal homo [3 + 2] dipolar cycloaddition we chose
nitrones, which have previously been shown to react with
strained cyclic molecules.9−12
Initially, nitrone 2 was combined with 1 in DMSO at 85 or
100 °C. After 3 days, the consumption of 1 was complete, and
the oxazabicyclo[3.2.1]octane (exo-3) was isolated as the
major component of a 5:1 mixture of diastereomers (Scheme 1
and Table 1, entry 3). Neither addition of Lewis acids (entries
5−11) nor bases (entries 12 and 13) improved the outcome
(e.g., Lewis base−housane adducts were usually observed in
the crude product). A concise survey of high-boiling polar
solvents identified sulfolane as the most suitable candidate,
delivering endo- and exo-3 in 64% total yield.
To explore the scope and limitations of this reaction, 1 was
reacted with a number of readily available nitrones in sulfolane
(Scheme 2, compounds 3−13). It was found that the
dihydroisoquinoline-nitrones were generally the most reactive,
while simpler cyclic nitrones gave products in modest yields
Figure 1. (A) Baran’s cyclopentylation reaction. (B) Strain-release
driven cycloadditions.
and the aniline-type cycloadduct 13 was not formed at all.
A particularly pleasing result was the installation of the new
quaternary stereocenter in compound 4.
In all of the oxazabicyclo[3.2.1]octane products, the exo
diastereomer was observed as the major component. This
Received: May 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01652
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Cycloaddition of Nitrone 2 with Housane 1
Scheme 2. Substrate Scope for the Cycloaddition, with
Nitrones, Relative Stereochemistry
Table 1. Evaluation of Conditions for the Cycloaddition
entry
solvent
additive (10%)
result
a
b
b
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
mixture 1/3 2:1
mixture 1/3 1:3
c
2
d
e
3
43% exo
ef
,
4
44% exo
ab
,
5
BF3·OEt2
Cu(OTf)2
mixture 1/3 2:1
ab
,
6
mixture 1/3 3:1
be
,
7
NiCl2(PPh3)2
18% exo
ab
,
8
ZnCl2
mixture 1/3 2:1
mixture 1/3 1:2
mixture 1/3 1.5:1
ab
,
9
AgSbF6
ab
,
10
11
12
13
14
15
16
17
(AuNTf2(PPh3))2−toluene
ab
,
PtCl2
DMAP
PPh3
mixture 1/3 1:1
ae
,
20% exo
mixture 1:3 1.3:1
ab
,
g
b
MeCN
mixture 1/3 1:1.4
g
b
dioxane
mixture 1/3 2:1
g
e
NMP
40% exo
ef
,
sulfolane
64% exo
a
b
c
d
e
1
85 °C. Based on crude H NMR. 30 h. 72 h. Full conversion.
f
g
Isolated yield. 120 °C. 120 h.
assignment is based on the isolation and ROESY-NMR
analysis of both diastereomers in each case. For the minor
endo-diastereomers, a through-space correlation was observed
between the methine proton α to the nitrogen and one of the
protons of the bridging methylene group. This correlation was
absent for the major diastereomers.
For our medicinal chemistry project, cycloadditions using
pyridine N-oxides13 such as 14 were also of interest, and these
were submitted to the same initial conditions (DMSO as
solvent, which proved superior to sulfolane) as the nitrones
(Scheme 3).
a
For DMSO.
Scheme 3. Cycloaddition−Elimination with Pyridine
N-Oxide 14
Not unexpectedly, the reaction did not halt at the
cycloadduct stage and presumed intermediate 15 rearomatized
to form cis-16 in 50% yield. The results with other pyridine
N-oxides are shown in Scheme 4 (compounds 16−24).
It became apparent that this reaction was sensitive to
electronic influence: alkyl substituents on the pyridine ring
are well tolerated in all positions and even sterically
encumbered species such as 20 were readily formed, while
electron-withdrawing substituents directly on the pyridine ring
gave a complex mixture of products from which only trace
amounts of the desired product could be isolated. Surprisingly,
compound 21 was formed in only low yield (<10%) and was
difficult to purify.
Compounds 16 and 19 could also be desulfonylated easily,
providing pyridine alcohols 29 and 30, respectively, as trans-
cyclopentanes (presumably via thermodynamic control at the
benzylic center).
In conclusion, we have developed a new variant of
stereoselective strain-release driven reactions (formal homo
[3 + 2] dipolar cycloadditions) which utilize housane (1) to
construct functionalized amino alcohols and pyridine-sub-
stituted cyclopentanes in two to three steps from simple and
easily available building blocks (nitrones and pyridine N-oxides
respectively). These pyridine and amino alcohols can be used,
To showcase the usefulness of this methodology,
oxazabicyclo[3.2.1]octanes 3 and 7 were desulfonylated,
reduced to the corresponding amino alcohols, and then
subsequently isolated as bis-acetates 26 and 28 (Scheme 5).
B
DOI: 10.1021/acs.orglett.9b01652
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
after further chemoselective manipulations, in medicinal
chemistry programs, as exemplified by the use of the oxidized
version of 29 (the ketone), in search for a PDE4 ligand.14
Scheme 4. Substrate Scope for the Cycloaddition and
Cycloaddition Elimination, with Pyridine N-Oxides,
Relative Stereochemistry
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01652.
Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mjes@lundbeck.com.
*E-mail: dt@kemi.dtu.dk.
Author Contributions
§S.C. and A.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the Innovation
Fund Denmark (Case No. 7038-00149B) and H. Lundbeck A/S.
We thank the Medicinal Chemistry department at H. Lundbeck
A/S for valuable resources and input. We also thank Dr. Henrik
Pedersen (H. Lundbeck A/S) for spectroscopic and analytical
assistance and Principal Scientist Per-Ola Norrby (AstraZe-
neca) for fruitful discussions.
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