Synthesis of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by sequential Ugi/[2+2] ene-enone photocycloadditions

Article abstract of DOI:10.1021/ol070164l

Figure presented We report a new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by combining the Ugi multicomponent reaction with [2+2] enone-olefin photochemical transformations. The overall seque

Full text of DOI:10.1021/ol070164l

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1299-1302
Synthesis of Novel and Uniquely
Shaped 3-Azabicyclo[4.2.0]octan-4-one
Derivatives by Sequential Ugi/[2
+2]
Ene Enone Photocycloadditions
−
Irini Akritopoulou-Zanze,* Alan Whitehead, Jan E. Waters, Rodger F. Henry, and
Stevan W. Djuric
Scaffold Oriented Synthesis and Structural Chemistry, Abbott Laboratories, R4CP,
AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-6099
irini.zanze@abbott.com
Received January 22, 2007
ABSTRACT
We report a new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by combining the
Ugi multicomponent reaction with [2 2] enone olefin photochemical transformations. The overall sequence is capable of creating up to five
stereocenters; however, in most cases, only two diastereomers are observed.
+
−
Isocyanide-based multicomponent reactions (IMCRs) coupled
with subsequent transformations provide highly diverse and
complex structures in only a few synthetic steps.1 One of
the most frequently used IMCRs is the Ugi reaction, a very
robust and versatile reaction that tolerates a wide variety of
functional groups.2
Heck,3 Ugi/intramolecular nitrile oxide cycloaddition,4 and
Ugi/intramolecular alkyne-azide cycloaddition5 sequences.
As part of our continuing efforts to develop synthetic
routes to access novel molecules, we became interested in
combining the Ugi reaction with photochemical transforma-
tions because intramolecular [2+2] cycloadditions were ex-
pected to provide novel molecular architectures and uniquely
shaped three-dimensional structures in two synthetic steps.
[2+2] Enone-olefin photochemical reactions are well
studied in both their inter- and intramolecular versions.6
Typically, the intramolecular photocycloadditions proceed
with high regioselectivity when the double bonds are
We have recently reported on several post-Ugi transforma-
tions to afford unique scaffolds based on sequential Ugi/
(1) For reviews, see: (a) Do¨mling, A. Chem. ReV. 2006, 106, 17-89.
(b) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210. (c)
Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80. (d) Zhu, J. Eur.
J. Org. Chem. 2003, 1133-1144.
(2) For early examples of post-Ugi modifications, see: (a) Tempest, P.;
Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42,
4963-4968. (b) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851-1854.
(c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere,
R. Tetrahedron Lett. 1998, 39, 7227-7230. (d) Hulme, C.; Morrissette, M.
M.; Volz, F. A.; Burns, C. J. Tetrahedron Lett. 1998, 39, 1113-1116. (e)
Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y. Tetrahedron Lett.
1998, 39, 7109-7112. (f) Strocker, A. M.; Keating, T. A.; Tempest, P. A.;
Armstrong, R. W. Tetrahedron Lett. 1996, 37, 1149-1152. (g) Short, K.
M.; Ching, B. W.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 7489-
7492.
(3) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45,
417-420.
(4) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 3421-3423.
(5) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 8439-8441.
(6) (a) Crimmins, M. T. Chem. ReV. 1988, 88, 1453-1473. (b) Fleming,
S. A.; Bradford, C. L.; Gao, J. J. Mol. Supramol. Photochem. 1997, 1, 187-
243. Griesbeck, A. G.; Fiege, M. Mol. Supramol. Photochem. 2000, 6, 33-
100.
10.1021/ol070164l CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/27/2007

connected with 2-4 atom tethers and with high diastereo-
selectivity providing in most cases a single diastereomer via
a 1,4 biradical intermediate. The photocycloaddition products
incorporate fused four-membered rings with at least three
new stereocenters and geometries that extend substituents
in numerous directions in three-dimensional space.
Table 2. Ugi Reactions and Subsequent [2+2]
Photocyclizations in MeOH upon Irradiation for 5 h
In this letter, we present, to our knowledge, the first
combination of an MCR reaction with a photochemical
transformation to access highly complex and novel azabicyclo-
[4.2.0]octan-4-one derivatives. We initiated our studies with
chromenone acetic acid 1 (Scheme 1). The Ugi reaction
Scheme 1. Sequential Ugi/[2+2] Ene-Enone
Photocycloadditions with
2-(7-Methoxy-2-oxo-2H-chromen-4-yl)acetic Acid 1
proceeded in moderate yields to provide adducts 2, which
were subjected to irradiation7 to yield a mixture of diaster-
eomers 3 and 4 as racemic mixtures.
Table 1. [2+2] Photocyclizations in Various Solvents upon
Irradiation for 5 h
a
Diastereomeric ratios of 3b/4b and 3c/4c were 3:1 based on 1H NMR.
b
c
Photocycloaddition was performed in 6:1 MeCN/MeOH for 12 h.
Photocycloaddition was performed in 4:1 MeOH/MeCN.
Although intramolecular photocycloadditions of systems
such as 2 are not known in the literature, we were pleased
to observe in all cases a single regio- and diastereoisomer
derived from the [2+2] photocycloaddition consistent with
previous observations on related systems.8,9
Using chromenone acetic acid 1 and p-chlorobenzaldehyde
as the aldehyde input, we next optimized the photocycload-
starting
material byproduct products products
yield %a
entry
solvent
yield %a
yield %a
ratiob
(7) The reaction was performed in a capped vial, sparged with argon,
and placed in 3-inch proximity to a medium pressure, 450 W, mercury
lamp. When the reaction was performed in an immersion well reactor
equipped with a quartz Pen-Ray 5.5 W, low-pressure, cold cathode, mercury
lamp (Penn, J. H.; Orr, R. D. J. Chem. Educ. 1989, 66, 86-88.), the reaction
was complete in 2 h. However, we preferred the former method due to the
convenience of using vials as well as the ability to perform multiple reactions
concurrently.
1
2
3
4
5
MeOH
MeCN
CH2Cl2
benzene
THF
7
32
40
35
68
0
5
7
6
11
80
37
46
23
14
1.3:1
1.2:1
1.3:1
1.1:1
1.1:1
a
1
b
Calculated based on isolated crude yield by H NMR. 3a over 4a.
(8) Haywood, D. J.; Reid, S. T. Tetrahedron Lett. 1979, 20, 2637-2638.
(9) Brandes, S.; Selig, P.; Bach, T. Syn. Lett. 2004, 14, 2588-2590.
1300
Org. Lett., Vol. 9, No. 7, 2007

dition reaction by evaluating a variety of solvents (Table 1).
The reaction was slow in most solvents, and an unidentifiable
byproduct was also formed. MeOH proved to be superior to
other solvents, provided a cleaner crude reaction and higher
yields, and became the solvent of choice. In some instances,
small amounts of acetonitrile were added to aid solubility.
Scheme 2. Sequential Ugi/[2+2] Ene-Enone
Photocycloadditions with
2-(2-Oxo-1,2-dihydroquinolin-4-yl)acetic Acida
Subsequent experiments with other allylamines provided
similar results. When the allylamines were further substituted
(entries 1 and 2, Table 2), we observed a stereoselectivity
with respect to the Ugi stereocenter favoring diastereomer 3
over 4. The structure of diastereomer 3b was unambiguously
assigned by X-ray crystallography (Figure 1). The stereo-
a Photocyclization was performed in MeOH for 5 h.
shaped structures. Furthermore, the sequence provided a
rapid, atom-economical way of providing such structures.
We also explored the utility of other carboxylic acid inputs
such as dihydroquinolone acetic acid 5 (Scheme 2) and
cyclohexenone carboxylic acid 7 (Scheme 3). Dihydroqui-
Scheme 3. Sequential Ugi/[2+2] Ene-Enone
Photocycloadditions with 3-Oxocyclohex-1-enecarboxylic Acida
Figure 1. X-ray structure of racemic 3b.
chemistry of the other diastereomer was assigned on the basis
of NMR observations. We observed similar 1H-13C and 1H-
1H correlations of the methyl protons of position 34 (Figure
1) to its environment in 3b and 4b, suggesting that the
stereochemistry at these centers is preserved. Additionally,
we have noted a substantial upfield shift of proton 20a of
3b at 1.67 ppm vs 4b at 3.06 ppm. This is consistent with
the X-ray where the aromatic ring protons 31 and 32 are in
close vicinity to proton 20a and provide a shielding effect.
Furthermore, NOE correlations between protons 31 and 32
and 20a are observed in 3b but not in 4b.10 The stereochem-
istries of structures 3a/4a and 3c/4c were assigned on the
basis of similar observations. On the basis of the above
findings, we speculated that the observed facial selectivity
is due to a favorable hydrophobic interaction between the
p-chlorophenyl substituent and the substituted alkene, which
is further intensified in polar solvents such as MeOH.
Remarkably, symmetric ketones such as acetone and
cyclohexanone worked just as well as their aldehyde
counterparts to provide only one diastereomer. In the case
of entry 3, Table 2, upon irradiation in MeOH, we have
observed predominantly transesterification of the lactone with
MeOH to provide the open phenol-methyl ester product in
84% yield. Ring opening was easily avoided by performing
the reaction in 6:1 MeCN/MeOH.
a Photocyclization was performed in MeOH for 5 h.
nolone acetic acid 5 provided the Ugi adduct in 41% yield
and the photocycloaddition product 6 in 87% yield as a 1.5:1
mixture of two diastereomers deriving from the Ugi stereo-
center (Scheme 2).
Ugi reactions with oxo-cyclohexene acid 711 (Scheme 3)
provided products 8 in moderate to good yields, and
subsequent photocycloadditions yielded compounds 9. Varia-
tion of carbon chain lengths of amine inputs (Table 3)
provided the opportunity to obtain different ring sizes upon
cycloaddition.12 Thus five-, six-, and seven-membered rings
(entries 1-3, Table 3, respectively) fused with cyclobutane
could easily be accessed in only two steps. In the case of
(11) Prepared by oxidation of cyclohexene carboxylic acid with CrO3
in AcOH/Ac2O and deprotection with aq LiOH in THF according to:
Fonteneau, L; Rosa, S.; Buisson, D. Tetrahedron: Assymetry 2002, 13,
579-585.
(12) (a) Le blanc, S.; Pete, J. P.; Piva, O. Tetrahedron Lett. 1993, 34,
635-638. (b) Faure, S.; Piva-Le Blanc, S.; Piva, O. Tetrahedron Lett. 1999,
40, 6001-6004.
An inspection of the X-ray structure of 3b gratifyingly
confirmed our initial expectations of obtaining uniquely 3D
(10) For a detailed description of stereochemical assignments and
justification, see Supporting Information.
Org. Lett., Vol. 9, No. 7, 2007
1301

Scaffolds such as 9 can be further functionalized by
reactions performed at the ketone group such as reductive
aminations, R-brominations, and subsequent heterocyclic ring
formations, Beckman rearrangements, etc.
Table 3. Ugi Reactions and Subsequent [2+2]
Photocyclizations in MeOH upon Irradiation for 5 h
In conclusion, we have developed a new methodology to
access highly functionalized fused ring systems in only two
synthetic steps. Despite the complexity of the products
formed, [2+2] photocycloaddition occurred with high or
complete diastereoselectivity with respect to the tri- and
tetrasubstituted cyclobutane ring systems. When substituted
allyl amines were employed, mild diastereoselectivity was
observed relative to the Ugi-formed stereocenter in which
two diastereomers were formed.
Acknowledgment. The authors would like to thank David
N. Whittern, structural chemistry, Abbott Laboratories, for
assistance with NMR interpretations and Dr. Paul R. West,
structural chemistry, Abbott Laboratories, for obtaining the
HR-MS spectra. A.W., department of chemistry, University
of Kansas, would like to thank Abbott Laboratories for a
summer internship position.
Supporting Information Available: Experimental pro-
cedures, stereochemical assignments, and X-ray and spectral
data for compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
a
Contains 20% of regioisomer 10a.13 b Contains 30% of diastereomer
11c.13
the five-membered ring, the other regioisomer was also
present in small amounts, whereas in the case of the seven-
membered ring, we also observed the formation of a different
diastereomer.13
OL070164L
(13) See Supporting Information.
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Org. Lett., Vol. 9, No. 7, 2007