Type 2 intramolecular N-acylnitroso diels-alder reaction: stereoselective synthesis of bridged bicyclic oxazinolactams.

Article abstract of DOI:10.1021/ol026075k

[reaction: see text] The type 2 intramolecular N-acylnitroso Diels-Alder reaction has been employed for the synthesis of substituted bridged bicyclic oxazinolactams. Upon oxidation of hydroxamic acid 6, a 3-benzylated oxazinolactam (7) was synthesized with complete diastereoselectivity. Elaboration of cycloadduct 7 liberated a cis-3,7-disubstituted azocin-2-one (9).

Full text of DOI:10.1021/ol026075k

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2637-2640
Type 2 Intramolecular N-Acylnitroso
Diels−Alder Reaction: Stereoselective
Synthesis of Bridged Bicyclic
Oxazinolactams
Chun P. Chow, Kenneth J. Shea,* and Steven M. Sparks
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
kjshea@uci.edu
Received April 25, 2002
ABSTRACT
The type 2 intramolecular N-acylnitroso Diels−Alder reaction has been employed for the synthesis of substituted bridged bicyclic oxazinolactams.
Upon oxidation of hydroxamic acid 6, a 3-benzylated oxazinolactam (7) was synthesized with complete diastereoselectivity. Elaboration of
cycloadduct 7 liberated a cis-3,7-disubstituted azocin-2-one (9).
Medium-ring nitrogen heterocycles occur in many natural
and unnnatural products and possess a broad spectrum of
medicinal and biological properties.1 Azocin-2-ones (eight-
membered lactams), in particular, have been used as sedatives
and anti-convulsant and anti-hypertensive agents.2 More
recently, disubstituted azocin-2-ones have been prepared as
peptide analogues to mimic the type VI â-turn conformation
of natural polypeptides.3 The preparation of eight-membered
rings by conventional cyclization methods of acyclic precur-
sors has presented considerable challenges to chemists due
to unfavorable enthalpic and entropic factors.4 Current
synthetic methodology for the preparation of this class of
compounds still remains substrate specific, and general
solutions for the regio-functionalization and stereocontrolled
synthesis have not been well established.5 Increasing interest
in eight-membered heterocycles has resulted in progress
toward synthesizing functionalized azocin-2-ones.6
We have been developing hetero type 2 intramolecular
Diels-Alder (IMDA) methodology for the synthesis of
medium ring heterocycles.7-9 Type 2 connectivity in the
IMDA cycloaddition10 provides an opportunity to control
both regio- and stereochemistry. As part of this program,
N-acylnitroso dienophiles have been employed for the
preparation of bridged bicyclic molecules.11 For example,
(5) (a) Alcaide, B.; Rodriguez-Ranera, C.; Rodriguez-Vicente, A.
Tetrahedron Lett. 2001, 42, 3081-3083. (b) Smalley, R. K. In Compre-
hensiVe Heterocyclic Chemistry; Katrytzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 7, Chapter 5, p 491. (c) Moore, J. A. In
ComprehensiVe Heterocyclic Chemistry; Katrytzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 1984; Vol. 7, Chapter 5, p 653. (d) Anastassiou,
A. G. In ComprehensiVe Heterocyclic Chemistry; Katrytzky, A. R., Rees,
C. W., Eds.; Pergamon: Oxford, 1984; Vol. 7, Chapter 5, p 709.
(6) Homsi, F.; Rousseau, G. J. Org. Chem. 1998, 63, 5255-5258.
(7) Bear, B. R.; Shea, K. J. Org. Lett. 2001, 3, 723-726.
(8) Lease, T. G.; Shea, K. J. J. Am. Chem. Soc. 1993, 115, 2248-2260.
(9) Shea, K. J.; Lease, T. G.; Ziller, J. W. J. Am. Chem. Soc. 1990, 112,
8627-8629.
(1) For a review on medium ring nitrogen heterocycles, see: Evans, P.
A.; Holmes, A. B. Tetrahedron 1991, 47, 9131-9166.
(2) Thorsett, E. D. et al. J. Med. Chem. 1986, 29, 251-260.
(3) (a) Derrer, S.; Davies, J. E.; Holmes, A. B. J. Chem. Soc., Perkin
Trans. 1 2000, 2943-2956. (b) Derrer, S.; Davies, J. E.; Holmes, A. B. J.
Chem. Soc., Perkin Trans. 1 2000, 2957-2967.
(10) (a) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed.
2001, 40, 821-849.
(11) Sparks, S. M.; Vargas, J. D.; Shea, K. J. Org. Lett. 2000, 2, 1473-
1475.
(4) (a) Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117-3125.
(b) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-102.
10.1021/ol026075k CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/11/2002

upon oxidation of N-hydroxy-6-methylene-7-octenamide, the
corresponding N-acylnitroso intermediate 1 undergoes spon-
taneous intramolecular cycloaddition to form the bridged
bicylic oxazinolactam (2) as a single regioisomer (Scheme
1). The cycloadduct contains both a bridgehead olefin and a
structure of the bridgehead oxazinolactam (2) can be used
to approximate the [4 + 2] cycloaddition transition state.15
Analysis of the X-ray crystal structure of oxazinolactam 2
revealed a close contact between the endo proton at C11
and the syn hydrogen at C3 (Scheme 1). This intimate proton
interaction suggested that substituents at position C2 in the
Diels-Alder precursor could introduce a bias in the stereo-
selectivity of the ensuing cycloaddition step.16
Scheme 1
The synthesis of an R-benzylated hydroxamic acid 6 was
undertaken to examine the effect (Scheme 2). Esterification
Scheme 2
bridgehead oxazinolactam functional group. In contrast, the
corresponding intermolecular Diels-Alder reaction gives an
equal mixture of regioisomers.11 The origin of the regio-
selectivity of the intramolecular cycloaddition can be ex-
plained in part by consideration that the estimated energy
of the 1,3-regioisomer (meta cycloadduct, 2) is 2.7 kcal mol-1
of 6-methylene-7-octenoic acid 48 followed by alkylation
(LDA, THF, -78 °C; BnBr) provided ester 5. Conversion
of 5 to hydroxamic acid 6 was accomplished by treatment
with NH2OH‚HCl and KOH in MeOH. Addition of hydrox-
amic acid 6 to a CHCl3 solution of n-Bu4NIO4 led to the
isolation of cycloadduct 7 in 85% yield as a single diaste-
reomer (100% ds).17
The 1,3-regiochemistry of cycloadduct 7 was determined
by two-dimensional homonuclear COSY experiments. Indi-
vidual off-diagonal signals allowed differentiation between
the two sets of diastereotopic protons at C9 (4.85 and 4.40
ppm) and C11 (4.07 and 3.66 ppm). The assignments of the
C9 protons were based on their unique cross-peaks that
correlated with the C8 vinylic hydrogen at 5.51 ppm. The
assignments of the C11 protons were strengthened in the
following stereochemical determination of cycloadduct 7
using NOE analysis.
lower than the 1,4-regioisomer (para cycloadduct, 3).12
A
portion of this difference in strain energy can be manifested
in the competing transition states leading to cycloadduct
formation.
In view of the importance of complex medium-ring
heterocycles, we are developing methods for their stereo-
and enantioselective synthesis. Specifically, we have exam-
ined the effect of tether substituents on the diastereoselec-
tivity of the N-acylnitroso cycloaddition. The introduction
of substituents has been found to influence the π-facial
selectivity of the type 2 IMDA reaction.13 We report the
synthesis of a series of substituted hydroxamic acid precur-
sors. The cycloaddition reaction of these precursors pro-
ceeded readily upon oxidation and resulted in moderate to
complete diastereoselectivity. These processes provide a
stereocontrolled entry into functionalized bridged bicyclic
oxazinolactams.
Irradiation of the C3 methine proton at 2.55 ppm resulted
in enhancement of the syn proton at C11 at 4.07 ppm
A concerted cycloaddition involves continuous overlap
between the π orbitals of the 2-substituted butadiene and
those of the nitroso dienophile.14 Since the strained cyclo-
adduct has relatively low conformational flexibility, the
(15) MMFF calculations suggested that the ground-state conformation
of cycloadduct 2 is approximately 6.1 kcal mol-1 lower in strain energy
than the nearest local minimum conformation.
(16) The carbon atoms R, â, and δ to the hydroxamic acid functionality
are referred to positions C2, C3, and C4, respectively. In accordance to the
IUPAC system, the corresponding atoms in the cycloadduct have changed
to positions C3, C4, and C5. See the numbering system shown in Scheme
1.
(12) Calculations were performed with GAUSSIAN 98. The structures
were optimized using the implemented B3LYP functional and 6-31G* basis
set.
(13) Shea, K. J.; Gauthier, D. R., Jr. Tetrahedron Lett. 1994, 35, 7311-
(17) The diastereoselectivity of all cycloadditions in this study was
determined by comparing the spectroscopic ratio of the C8 vinylic protons
in crude reaction mixtures by H NMR.
7314.
1
(14) Leach, A. G.; Houk, K. N. J. Org. Chem. 2001, 66, 5192-5200.
2638
Org. Lett., Vol. 4, No. 16, 2002

(6.0%).18 Enhancement of the methine proton at C3 (3.6%)
was also observed in the converse experiment by irradiating
the same C11 hydrogen. This establishes the benzyl sub-
stituent at C3 is in an anti relationship with respect to the
methylene bridge (C11).
factor, we have synthesized 2-benzyloxy hydroxamic acid
derivative 10.
Oxidation and cycloaddition of 10 produced a single anti
diastereomer 11, 100% ds (Scheme 4). In the transition state
Elaboration of cycloadduct 7 was carried out to corroborate
the stereochemical and regiochemical assignments by the
conversion to an azocin-2-one (Scheme 3). Catalytic hydro-
Scheme 4
Scheme 3
for this cycloaddition, the syn product would be favored due
to dipole-dipole repulsion. Since the anti product is found
exclusively with carbon and oxygen substituents in both
reactions, it appears that sterics dominate the origin of
stereoselectivity in 2-substituted derivatives.
The influence of substituents at tether position C3 is less
clear in the competing cycloaddition transition states that
lead to formation of syn and anti products. The requisite
Diels-Alder precursor 14 was synthesized by aldol addition
of the enolate of 9,10-dimethylanthracene adduct 1220 to
4-methylene-5-hexen-1-al 1321 (Scheme 5). The correspond-
genation of cycloadduct 7 afforded saturated bicyclic ox-
azinolactam 8 in 80% yield.19 Irradiation of the methine
proton (2.63 ppm) at C3 R to the benzyl group resulted in
the enhancement of the syn proton (4.14 ppm) of the
methylene bridge, consistent with the stereochemistry ob-
served in precursor 7. Na(Hg) amalgam reduction of 8,
induced cleavage of the N-O bond and provided a cis-3,7-
disubstituted azocin-2-one (9) as a single diastereomer in
80% yield.
Scheme 5
Assignment of the cis configuration in 9 from reduction
of 8 is based on the assumed configurational integrity of the
stereocenters at C3 and C7 during cleavage of the N-O
bond. The structure of an azocin-2-one 9 was suggested by
1
the presence of hydroxyethyl and benzyl fragments in H
NMR. In addition, when lactam 9 was subjected to CIMS,
a molecular ion involving the loss of 45 amu was observed,
consistent with the fragmentation of a -CH2CH2OH group.
These results establish that formation of 9 derived from
elaboration of a bicyclo[5.3.1] adduct (1,3-regioisomer),
oxazinolactam 7 (Scheme 3). The formation of oxazinolactam
7, an anti diastereomer, is consistent with the transition-state
model based on the structure of the cycloadduct.
Rationalization of stereoselectivity of the cycloaddition is
based on steric interactions that develop in our working
model for the transition state. Since heteroatom substituents
are also used in this study, other factors such as dipole-
dipole interactions could also contribute to the stereoselec-
tivity of the reaction. To evaluate the importance of this
(18) NOE experiments were conducted using the DPFGSE method with
mixing times (D8) of 0.5 s.
ing secondary alcohol was protected as a tert-butyldimeth-
ylsilyl ether (14). The Diels-Alder precursor was generated
(19) Addition to bridgehead olefins occurs with complete exo-facial
selectivity. See: (a) Shea, K. J. Tetrahedron 1980, 36, 1683-1715. (b)
Shea, K. J.; Beauchamp, P. S.; Lind, R. S. J. Am. Chem. Soc. 1980, 102,
4544-4546. (c) Shea, K. J.; Fruscella, W. M.; Carr, R. C.; Burke, L. D.;
Cooper, D. K. J. Am. Chem. Soc. 1987, 109, 447-452. (d) Whitney, J. M.;
Parnes, J. S.; Shea, K. J. J. Org. Chem. 1997, 62, 8962-8963.
(20) Keck, G. E.; Webb, R. R.; Yates, J. B. Tetrahedron 1981, 37, 4007-
4016.
(21) Bertele, R. A.; Schudel, P. S. HelV. Chim. Acta 1967, 50, 2445-
2456.
Org. Lett., Vol. 4, No. 16, 2002
2639

in situ by heating adduct 14 in benzene to reflux. The
subsequent intramolecular cycloaddition led to the formation
of two diastereomers in a 4:1 ratio in 84% combined yield.
Purification by silica gel column chromatography allowed
the separation of syn-15 and anti-15. Analysis of the X-ray
crystal structure of the major product established the syn
stereochemistry (syn-15) between the silyloxy group at C4
and the methylene bridge (C11).
Scheme 6
In the COSY spectrum of the minor product (anti-15), the
presence of cross-peaks between the C8 vinylic proton (5.43
ppm) and the C9 hydrogens (4.28 and 4.76 ppm) establishes
1
their proximity. The H NMR of anti-15 revealed an AB
system for the two diastereotopic protons at C11 (3.67 and
3.97 ppm). The anti stereochemistry of the cycloadduct was
assigned on the basis of a 3.9% signal enhancement of the
C11 syn hydrogen at 3.97 ppm by irradiating the C4 methine
proton at 4.72 ppm. The C3 substitution in the Diels-Alder
precursor exerted only a moderate (4:1) influence at 80 °C
on the diastereoselectivity of cycloaddition in favor of the
syn product (syn-15).
Inspection of the X-ray crystal structure of oxazinolactam
2 also revealed a close contact between the endo proton at
C11 and the syn hydrogen at C5 (Scheme 1). The contact is
less than that between the C11 endo proton and the C3 syn
hydrogen. Nevertheless, substitution at position C4 in the
tether may also lead to a diastereoselective cycloaddition.
The 4-benzyloxyhydroxamic acid 20 was targeted for
synthesis (Scheme 6). Enantioselective isoprenylation22 of
4-(tert-butyldimethylsiloxy)butanal 1623 with diisopinocam-
pheylborane 17 gave homoallylic alcohol (R)-(-)-18 in 92%
ee.24 Alcohol protection, desilation, and Jones oxidation
afforded carboxylic acid 19. Esterification followed by
treatment with basic hydroxylamine furnished hydroxamic
acid 20. Subsequent oxidation of Diels-Alder precursor 20
with n-Bu4NIO4 in CHCl3 at 0 °C provided two diastereomers
in a 3.7:1 ratio favoring syn-21 in 84% combined yield. The
two cycloadducts were separated by preparative thin-layer
chromatography using CHCl3/ethyl acetate (9:1, v/v).
The basis of the structural assignments of syn- and anti-
21 was analogous to those used to identify cycloadducts 7
(Scheme 2) and anti-15 (Scheme 4). The stereochemistry of
cycloadducts 21 was secured by NOE analysis. In syn-21,
irradiation of the benzilic protons at 4.53 ppm resulted in
the enhancement of the C11 syn proton at 3.67 ppm (4.1%).
Saturating either the C5 methine proton (4.01 ppm) or the
C11 syn proton did not give increase in the intensity of the
reciprocal proton signals. These NMR results allowed the
assignment of a syn relationship of the benzyloxy group at
C5 with respect to the methylene bridge (C11). In the minor
product (anti-21), enhancement of the C11 syn proton at 3.75
ppm was observed by irradiating the C5 methine proton at
3.88 ppm (3.2%), consistent with the anti stereochemistry
assigned in the cycloadduct.
In contrast with the 2-substituted Diels-Alder precursor,
substitution at position C4 of hydroxamic acid 20 induced a
slight bias in the cycloaddition favoring the formation of syn-
21. This observed diastereoselectivity is opposite to that
predicted on the basis of the structure of the cycloadduct
and calls attention to the limitation of this model.
In summary, we have developed approaches for the
introduction of substituents at positions C3-5 in oxazino-
lactams by the type 2 intramolecular N-acylnitroso Diels-
Alder reaction. Complete diastereoselectivity for the C2
substituted precursor was observed, leading to the formation
of an anti-substituted oxazinolactam. The substituted bridged
bicyclic oxazinolactams will form the basis of the synthesis
of complex hetereocycles.
Acknowledgment. This research was supported in part
by a grant from the National Institutes of Health. We are
grateful to Dr. Joseph W. Ziller for assistance with the X-ray
crystallographic work. S.M.S. was supported by a graduate
fellowship sponsored by Pharmacia, and C.P.C. thanks Xerox
Corp. for a Xerox Technical Minority Scholarship.
(22) (a) Brown, H. C.; Randad, R. Tetrahedron 1990, 46, 4463-4472.
(b) Brown, H. C.; Randad, R. Tetrahedron Lett. 1990, 31, 455-458.
(23) Tori, M.; Toyoda, N.; Sono, N. J. Org. Chem. 1998, 63, 306-313.
(24) Determined as (R)-(+)-R-methoxy-R-(trifluoromethyl)phenylacetate
(MTPA) derivative on capillary GC.
OL026075K
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Org. Lett., Vol. 4, No. 16, 2002