Interesting behavior of α,β-unsaturated oximes in intramolecular [4 + 2] cycloaddition reactions

Article abstract of DOI:10.1021/ol049640n

Equation presented. Intramolecular [4 + 2] cycloaddition using α,β-unsaturated oximes was explored. The reactions proceeded under unusually facile conditions to furnish the nitrones. The latter were subsequently reacted with DMAD to afford [3 + 2] cycload

Full text of DOI:10.1021/ol049640n

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1931-1934
Interesting Behavior of r,â-Unsaturated
Oximes in Intramolecular [4 + 2]
Cycloaddition Reactions
David Franc¸ois, Amy Maden, and William V. Murray*
Johnson & Johnson Pharmaceutical Research and DeVelopment, LLC,
1000 Route 202, Box 300, Raritan, New Jersey 08869
wmurray@prdus.jnj.com
Received February 27, 2004 (Revised Manuscript Received May 4, 2004)
ABSTRACT
Intramolecular [4 + 2] cycloaddition using r,â-unsaturated oximes was explored. The reactions proceeded under unusually facile conditions
to furnish the nitrones. The latter were subsequently reacted with DMAD to afford [3 + 2] cycloaddition products.
The intramolecular Diels-Alder (IMDA) reaction has proven
to be useful in the regio- and stereoselective construction of
highly substituted bicyclic and polycyclic ring systems.1 The
advantages of an intramolecular reaction over its inter-
molecular counterpart are well documented.2 Over the past
15 years, considerable effort has gone into the development
of the Diels-Alder reaction of 1-azadienes.3 The latter,
unlike their counterpart 2-azadienes, are known for their
reluctance to undergo [4 + 2] cycloaddition reactions. The
introduction of a nitrogen atom at position 1 of the diene
creates an electron-deficient π-system and explains why
1-azadienes are characteristically poor dienes in the normal
[HOMOdiene-controlled] Diels-Alder reaction with electron-
deficient dienophiles. Important contributions by several
groups have shown that this problem can be circumvented
by introducing either electron-donating4 or -withdrawing5
substituents on the imine nitrogen. Considerable difficulties
have been encountered in the extension of those approaches
to R,â-unsaturated oximes4,5a,e because of their reduced
thermodynamic driving force compared to typical dienes and
also due to possible rearrangements to conjugated enamines
or to 2-azadienes.6,7
Accordingly, this particular class of 1-azadienes has drawn
very little attention, and to date, only one example of an
R,â-unsaturated oxime involved in an intermolecular Diels-
Alder reaction has been reported; but the authors do not
report spontaneous isomerization to a nitrone.8
It would be anticipated that the substitution of an R,â-
unsaturated imine with an electron-donating substituent such
as an alcohol group would accentuate the electron-rich nature
of the heterodiene and thus preferentially promote a
(4) (a) Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez, L. Tetra-
hedron Lett. 1982, 23, 3261. (b) Boger, D. L.; Zhu, Y. Tetrahedron Lett.
1991, 32, 7643.
(5) (a) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J.
Am. Chem. Soc. 1991, 113, 1713. (b) Boger, D. L.; Nakahara, S. J. Org.
Chem. 1991, 56, 880. (c) Boger, D. L.; Curran, T. T. J. Org. Chem. 1990,
55, 5439. (d) Boger, D. L.; Corbett, W. L.; Wiggins, J. M. J. Org. Chem.
1990, 55, 2999. (e) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989,
111, 1517.
(1) For reviews on Diels-Alder reaction, see: (a) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668. (b) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew.
Chem., Int. Ed. 2001, 40, 820. (c) Roush, W. R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, pp 513-550.
(2) Page, M. I. Chem. Soc. ReV. 1973, 2, 295.
(3) For a general discussion of Diels-Alder reactions of 1-azadienes,
see: (a) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259. (b)
Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Academic Press: San Diego, 1987; Chapter 9.
(6) Jung, M. E.; Shapiro, J. J. J. Am. Chem. Soc. 1980, 102, 7862.
(7) Cheng, Y.-S.; Fowler, F. W.; Luppo, A. T.J. Am. Chem. Soc. 1981,
103, 2090.
(8) Kusurkar, R. S.; Bhosale, D. K. Tetrahedron Lett. 1991, 32, 3199.
10.1021/ol049640n CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/15/2004

HOMOdiene-controlled Diels-Alder reaction with an electron-
deficient dienophile (Figure 1).
nary communication, we disclose the first examples of R,â-
unsaturated oximes involved in IMDA reactions to produce
bicyclic nitrones. In our studies, no trace of the expected
allylic hydroxylamines were found. These IMDA reactions
apparently occur via the enamine intermediate (Figure 1) and
rearrange to the nitrone. This facile rearrangement, due to
an interaction between the lone pair of the nitrogen atom
and the π system, is well documented, particularly when no
enamine-stabilizing group is present.10
Figure 1. Proposed Aza-Diels-Alder Reaction of R,â-Unsaturated
The requisite starting materials 2a,b were readily obtained
from the corresponding NH-Boc-protected L-amino acids
1a,b as described previously (Scheme 1).11 Formation of the
corresponding R,â-unsaturated oximes took place upon
condensation of hydroxylamine hydrochloride with 2a,b to
give, in moderate yields, a separable mixture of (E)-oximes
3a,b as the minor isomers and (Z)-oximes 4a,b as the major
isomers. The E/Z stereochemistry of these oximes was
determined by one-dimensional difference NOE experiments
in DMSO-d6.
Oximes.
As part of our ongoing program to expand the synthetic
utility of optically active amino acid-derived trienes in IMDA
reactions,9 we set out to study the behavior of four chiral
nonracemic 1-azadienes, namely, the valine- and phenyl-
alanine-derived precursors 3a,b and 4a,b (Scheme 1). The
Surprisingly, while the (Z)-oximes 4a and 4b were stable
indefinitely when stored at room temperature, the (E)-oximes
3a and 3b were exceptionally reactive and underwent a
cycloaddition reaction within a few hours, even at 0 °C. Only
storage at -78 °C prevented these compounds from reacting
Scheme 1. Synthesis of Four New Chiral Nonracemic
1-Azadienesa
1
and allowed us to carry out H, 13C, and one-dimensional
NOE experiments. The transformation, which occurred either
in solution in CH2Cl2 or neat at room temperature, did not
lead to the anticipated formation of a ∆2-piperidine product.
Instead, starting from 3a, an unexpected product was
formed in 30% yield. This product was identified as the
nitrone 5 through NMR studies. This presumably proceeds
through the formation of an unstable endocyclic ∆2-piperi-
dine enamine 5′ that undergoes tautomerization to furnish
the nitrone 5 (Scheme 2). Related bicyclic nitrones have been
reported in the literature.12
Scheme 2. [4 + 2]/[3 + 2] Sequence with the (E)-Oxime 3a
a Reagents and conditions: (a) isobutyl chloroformate, 4-meth-
ylmorpholine, MeNH(OMe)‚HCl, CH2Cl2, 87%; (b) LAH, THF,
-78 °C, 82%; (c) (EtO)2P(O)CH2CO2Et, t-BuOK, THF, 0 °C to
rt, 70%; (d) 50% TFA in CH2Cl2, rt then NaHCO3, 95%; (e)
PhCHO, NaBH4, EtOH, 0 °C, 86%; (f) EDCI, HOAT, 3-acetyl
acrylic acid, DMF, 0 °C to rt, 80%; (g) NH2OH‚HCl, NaHCO3,
EtOH 50% aq, 0 °C to rt, 76%.
presence of a stereocenter in these triene precursors at the
allylic position of the dienophile should allow for discrimina-
tion of the diastereotopic faces of the reacting diene and
dienophile. Moreover, in IMDA reactions, the nature of the
tether linking the diene and dienophile often influences the
reactivity of the substrate and the structure of the transition
state and, thus, the stereochemical outcome. In this prelimi-
The optically active nitrone presents numerous opportuni-
ties for synthetic manipulations. At this point, we decided
to subject the diastereomerically pure nitrone 5 to 1,3-dipolar
cycloaddition13 in order to both chemically prove the
structure of the nitrone moiety and evaluate the reactivity
of the asymmetric nitrone. Reaction of 5 with dimethyl
(9) Murray, W. V.; Mishra, P. K.; Sun, S.; Maden, A. Tetrahedron Lett.
2002, 43, 7389.
1932
Org. Lett., Vol. 6, No. 12, 2004

acetylenedicarboxylate (DMAD) afforded isoxazoline 6 as
the only identifiable compound in 52% yield.
nitrones 5, 7, and 8. These structures have a rigid conforma-
tion, leading to efficient shielding of one of the nitrone faces.
The high π-facial selectivity of these cycloaddition reactions
seems to be dictated by the ester group adjacent to the dipole.
The dipolarophile thus approaches preferentially the less
hindered face (opposite face to the ester group), which for 5
and 7 is the re face and for 8 is the si face (Figure 2).
As previously observed for 3a, the phenylalanine-derived
precursor 3b spontaneously cyclized at room temperature
1
either in CH2Cl2 solution or neat. H NMR showed the
existence of a mixture of two isomers 7 and 8 (ratio 2.5:1),
which could not be separated by either flash chromatography
or HPLC. We found the mixture of nitrones to be relatively
unstable at room temperature, and they had to be derivatized
soon after isolation. The structural conformation and the
relative stereochemistry of 7 and 8 were established by
derivatization of their mixture with DMAD. This led to the
formation of two separable and characterizable isoxazolines
9 and 10 (ratio 2.5:1) in 70% yield and allowed us by analogy
to establish the stereochemistry of nitrones 7 and 8 (Scheme
3).
Scheme 3. [4 + 2]/[3 + 2] Sequence with the (E)-Oxime 3b
Figure 2. π-Facial Selectivities Accounting for the Formation of
Isoxazolines 6, 9, 10, 12, and 13.
Although (Z)-oximes exhibit a less pronounced intrinsic
reactivity at room temperature, we observed, in the case of
4a, that heating in acetic acid at 100 °C cleanly provided
the [4 + 2] cycloadduct 11 as a single diastereomer in 77%
yield.14 Surprisingly, the stereochemistry of the ester group
in 11 is inverted compared with that of nitrone 5. When
compound 5 was subjected to acetic acid at 100 °C for 4 h,
nitrone 11 was recovered in quantitative yield (Scheme 4).
Scheme 4. Epimerization of 5 in Acidic Medium
It appears that 1,3-dipolar cycloaddition of 7 and 8 takes
place with complete stereoselectivity. This result is analogous
to that of 5 in terms of stereoselectivity. As a consequence,
a single stereoisomer resulted from each of these bicyclic
This could indicate an initial isomerization of 4a to 3a,
cycloaddition, and subsequent epimerization.
The thermal cycloaddition between 11 and DMAD leads
to the formation of two stereoisomers 12 and 13 in 76% yield
(10) (a) Wright, S. W.; Harris, R. R.; Kerr, J. S.; Green, A. M.; Pinto,
D. J.; Bruin, E. M.; Collins, R. J.; Dorow, R. L.; Mantegna, L. R.; Sherk,
S. R.; Covington, M. B.; Nurnberg, S. A.; Welch, P. K.; Nelson, M. J.;
Magolda, R. L. J. Med. Chem. 1992, 35, 4061. (b) Padwa, A.; Wong G. S.
K. J. Org. Chem. 1986, 51, 3125. (c) Reamer, R. A., Sletzinger, M., Shinkai,
I. Tetrahedron Lett. 1980, 21, 3447.
(13) For reviews of 1,3-dipolar cycloadditions, see: (a) Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley: New York,
2003; Vol. 59. (b) Karlsson, S.; Hogberg, H.-E. Org. Prep. Proced. Int.
2001, 33, 103. (c) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98,
863. (d) Frederickson, M. Tetrahedron 1997, 53, 403.
(11) Murray, W. V.; Mishra, P. K.; Turchi, I. J.; Sawicka, D., Maden,
A.; Sun, S. Tetrahedron 2003, 59, 8955.
(12) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.; Pardo, C.;
Sa´ez, E.; Torres, M. R. J. Org. Chem. 2002, 67, 7004.
(14) It is worth noting that a simple treatment of 4a in acetic acid at
room temperature does not produce any cycloadduct.
Org. Lett., Vol. 6, No. 12, 2004
1933

of enzyme inhibitors15 or NMDA receptor antagonists.16
Interestingly, all of the final cycloadducts 6, 9, 10, 12, and
13 could open a direct route to highly substituted pipecolinic
acid esters via N-O bond breaking.
Scheme 5. [4 + 2]/[3 + 2] Sequence with the (Z)-oxime 4a
This IMDA/1,3-dipolar cycloaddition sequence gives ac-
cess to complex functionalized azapolycyclic systems. The
reaction proceeds through the formation of three carbon-
carbon bonds and four stereogenic centers in a process that
is unprecedented in the chemistry of R,â-unsaturated oximes
and in their proficiency in aza Diels-Alder reactions.
The above results demonstrate that the stereochemical
outcome of the IMDA reactions is governed by a combina-
tion of factors: (1) the reaction conditions and (2) the nature
of the starting amino acid. As we observed in earlier work,17
a better diastereofacial selectivity for the IMDA was observed
with the isopropyl group than with the benzyl group
presumably due to subtle steric effects in the transition
structures inherent to the size difference of these two groups.
As for the [3 + 2] cycloaddition reactions, the high degree
of facial discrimination observed is governed by the ester
function adjacent to the reacting center.
(ratio 1/0.28) (Scheme 5). The poor stereoinduction achieved
with cyclic nitrone 11 is in contrast with all of our examples
described herein. It is reasonable to justify this low π-facial
selectivity with steric hindrance on both sides due to the
isopropyl and ester groups.
In summary, we have shown the first examples of IMDA
reactions of R,â-unsaturated oximes. Theoretical calculations
to gain insight into the differences of reactivity between the
(Z)- and (E)-oximes are underway and will be reported in
due course as well as a full account of other cycloadditions.
Although the isopropyl group is remote from the reactive
center, its bulk tends to partially block the upper face (si
face). This presumably explains why cycloadduct 13 was
formed through an approach of DMAD on the re face. It is
interesting to note the subtle difference of behavior between
the two nitrones 8 and 11. The dipolarophile is not able to
efficiently differentiate between the si and re faces of the
nitrone 11, whereas it does for the nitrone 8. This observation
indicates that, when the ester group is positioned on the face
opposite to the benzyl group or isopropyl group, changing
from a benzyl group to a sterically more hindered isopropyl
group decreases the stereofacial selectivity (Figure 2).
These new polycycles, encompassing the piperidine ring,
could allow rapid access into building blocks and/or biologi-
cally active compounds. Much attention has been focused
on unnatural pipecolic acid derivatives substituted on the
piperidine ring as useful building blocks for the synthesis
Supporting Information Available: Complete experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL049640N
(15) Gillard, J.; Abraham, A.; Anderson, P. C.; Beaulieu, P. L.; Bogri,
T.; Bousquet, Y.; Grenier, L.; Guse, I.; Lavalle´e, P. J. Org. Chem. 1996,
61, 2226.
(16) Skiles, J. W.; Giannousis, P. P.; Fales, K. R. Bioorg. Med. Chem.
Lett. 1996, 6, 963.
(17) Murray, W. V.; Sun, S.; Turchi, I. J.; Brown, F. K.; Gauthier, A.
D. J. Org. Chem. 1999, 64, 5930.
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