3-Hydroxy-4-pyrones as precursors of 4-methoxy-3-oxidopyridinium ylides. An expeditious entry to highly substituted 8-azabicyclo[3.2.1]octanes

Article abstract of DOI:10.1021/jo960854v

3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.

Full text of DOI:10.1021/jo960854v

6114
J . Org. Chem. 1996, 61, 6114-6120
3-Hyd r oxy-4-p yr on es a s P r ecu r sor s of
4-Meth oxy-3-oxid op yr id in iu m Ylid es. An Exp ed itiou s En tr y to
High ly Su bstitu ted 8-Aza bicyclo[3.2.1]octa n es
Antonio Rumbo, Antonio Mourin˜o, Luis Castedo,* and J ose´ L. Mascaren˜as*,1
Departamento de Quı´mica Orga´nica y Seccio´n de Alcaloides del CSIC, Universidad de Santiago
de Compostela, 15706 Santiago de Compostela, Spain
Received May 8, 1996X
3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones,
can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl
trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides
are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the
synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns
of these frameworks might allow their divergent conversion to a variety of natural and non-natural
tropane alkaloids.
Sch em e 1
In tr od u ction
Whereas the Diels-Alder reaction has been of major
utility in the synthesis of both carbo- and heterocyclic
six-membered rings, cycloaddition reactions that form
seven-membered rings have been much less common.2
Recently, we reported a new, practical, stereoselective
route to highly functionalized [3.2.1] oxabicyclic systems
(2a , Scheme 1) based on the thermal [5 + 2] cycloaddition
of 3-alkoxy-4-pyrones to temporarily connected alkenes.3
The simplicity of the process and the ready availability
of the starting pyrones, coupled to the rich but differenti-
ated functionalization of the cycloadducts, augurs inter-
esting synthetic applications of this methodology.4
On the basis of these precedents, and bearing in mind
the presumable rapid accessibility of 3-alkoxy-4-pyri-
dones (1b) from the corresponding pyrones,5 we decided
to investigate the feasibility of using the former as “off-
the-shelf” five-carbon cycloaddition precursors of highly
functionalized 8-azabicyclo[3.2.1]octane skeletons (2b).
This was of interest because this bicyclic system is the
characteristic structural element of the tropane alkaloids,
an important family of bioactive natural products.6
Although a large number of interesting methods for the
synthesis of tropane alkaloids have already been devel-
oped,7 they are mostly inappropriate for the rapid as-
sembly of highly substituted analogs. We hoped that the
above approach might supplement the current strategies
by providing a novel and expeditious entry to a variety
of highly functionalized tropane derivatives.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) FAX: 34-81-595012. E-mail: qojoselm@usc.es.
(2) For [4C + 3C] cycloadditions, see: (a) Desimoni, G.; Tacconi, G.;
Barco, A.; Pollini, G. P. In Natural Product Synthesis through Pericyclic
Reactions; Marjorie, C. C., Ed.; ACS Monograph; American Chemical
Society: Washington, DC, 1983; pp 255-265. (b) Hosomi, A.; Tominaga,
Y. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I. A.,
Eds.; Pergamon: New York, 1991; Vol. 5, Chapter 5.1. (c) Mann, J .
Tetrahedron 1986, 42, 4611. (d) Harmata, M. In Advances in Cycload-
dition; Lautens, M., Ed.; J AI: Greenwich, 1995; Vol 4. (e) Molander,
G. A.; Cameron, K. O. J . Am. Chem. Soc. 1993, 115, 830. For [5C +
2C] annulations, see: (f) Sammes, P. G. Gazz. Chim. Ital. 1986, 119,
109. (g) Thomas, E. J .; Mortlock, S. V.; Seckington, J . K. J . Chem. Soc.,
Perkin Trans. 1 1988, 2305. (h) Padwa, A.; Fryxell, G. E.; Zhi, H. J .
Am. Chem. Soc. 1990, 112, 3100. (i) Wender, P. A.; McDonald, F. E. J .
Am. Chem. Soc. 1990, 112, 4956. (j) Wender, P. A.; Mascaren˜as, J . L.
J . Org. Chem. 1991, 56, 6267. (k) Wender, P. A.; Mascaren˜as, J . L.
Tetrahedron Lett. 1992, 33, 2115. (l) Engler, T. A.; Combrink, K. D.;
Letavic, M. A.; Lynch, K. O.; Ray, J . E. J . Org. Chem. 1994, 59, 6567.
(m) Engler, T. A.; Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J .
P. J . Org. Chem. 1994, 59, 6588.
(3) Rumbo, A.; Castedo, L.; Mourin˜o, A.; Mascaren˜as, J . L. J . Org.
Chem. 1993, 58, 5585.
(4) These cycloadducts can be transformed into sesquiterpene
precursors or stereochemically rich 2,3,5-trisubstituted tetrahydro-
furans: Rumbo, A.; Castedo, L.; Mourin˜o, A.; Mascaren˜as, J . L.
Unpublished results.
(5) Several recent articles concerning the preparation of biologically
relevant chelators describe the transformation of 3-hydroxy-4-pyrones
into 3-hydroxy-4-pyridones: (a) Nelson, W. O.; Karpishing, T. B.;
Rettig, S. J .; Orvig, C. Can. J . Chem. 1988, 66, 123. (b) Dobbin, P. S.;
Hider, R. C.; Hall, A. D.; Taylor, P. D.; Sarpong, P.; Porter, J . B.; Xiao,
G.; Van der Helm, D. J . Med. Chem. 1993, 36, 2448. (c) Kontoghiorghes,
G. J .; Sheppard, L. Inorg. Chim. Acta 1987, 136, L11-L12. (d) Molenda,
J . J .; J ones, M. M.; J ohnston, D. S.; Walker, E. M.; Cannon, D. J . J .
Med. Chem. 1994, 37, 4363.
Resu lts a n d Discu ssion
In order to test the feasibility of the approach, pyridone
7 was synthesized from commercially available kojic acid
(3) following the steps shown in Scheme 2. Reaction of
the chloropyrone 4 with allylmercaptan and triethy-
(6) For leading references to tropane alkaloids, see: (a) Fodor, G.;
Dharanipragada, R. Nat. Prod. Rep. 1994, 11, 443. (b) Lounasma, M.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1988;
Vol. 33, pp 1-81. (c) Lounasma, M.; Tamminen, T. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol. 44, p 1. (d)
Stoelwinder, J .; Roberti, M.; Kozikowski, A. P.; J ohnson, K. M.;
Bergmann, J . S. Bioorg. Med. Chem. Lett. 1994, 4, 303.
(7) For recent advances in tropane alkaloid synthesis, see: (a) Iida,
H.; Watanabe, Y.; Kibayashi, C. J . Org. Chem. 1985, 50, 1818. (b)
Kozikowski, A. P.; Xiang, L.; Tanaka, J .; Bergman, J . S.; J ohnson, K.
M. Med. Chem. Res. 1991, 1, 312. (c) Kozikowski, A. P.; Xiang, L.;
Tanaka, J .; Bergman, J . S.; J ohnson, K. M. Med. Chem. Res. 1991, 1,
312. (d) J ustice, D. E.; Malpass, J . R. Tetrahedron Lett. 1995, 36, 4689.
(e) Carroll, F. I.; Kotian, P.; Dehgshani, A.; Gray, J . L.; Kuzemko, M.
A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J . W. Kuhar, M.
J . J . Med. Chem. 1995, 38, 379. (f) Herna´ndez, A. S.; Thaler, A.;
Castells, J .; Rapoport, H. J . Org. Chem. 1996, 61, 314. (g) Tuffiarello,
J . J .; Mullen, G. B.; Tegleer, J . J .; Trybulski, E. J .; Wong, S. C.; Asrof,
Ali, S. J . Am. Che. Soc. 1979, 101, 2435. (h) Davies, H. M. L.; Saikali,
E.; Young, W. B. J . Org. Chem. 1991, 56, 5696. (i) Davies, H. M. L.;
Huby, N. J . S. Tetrahedron Lett. 1992, 33, 6935. (j) J ung, M. E.;
Longmei, Z.; Tangsheng, P.; Uiyan, Z.; Yan, L.; J ingyu, S. J . J . Org.
Chem. 1992, 57, 3528. (k) Davies, H. M. L. Tetrahedron 1993, 49, 5203.
(l) Davies, H. M. L.; Saikali, E.; Huby, N. J . S.; Gilliat, V. J .; Matasi,
J . J .; Sexton, T.; Childers, S. R. J . Med. Chem. 1994, 37, 1262.
S0022-3263(96)00854-7 CCC: $12.00 © 1996 American Chemical Society

Entry to Highly Substituted 8-Azabicyclo[3.2.1]octanes
J . Org. Chem., Vol. 61, No. 18, 1996 6115
Sch em e 2a
Ta ble 1. Cycloa d d ition of P yr id in iu m Sa lts 12 a n d 13 to
Sever a l Dip ola r op h iles
products
(exo:endo)
combined
yield (%)
salt
dipolarophile
12
12
12
12
13
13
N-phenylmaleimide
acrylonitrile
methyl acrylate
phenyl vinyl sulfone
N-phenylmaleimide
acrylonitrile
14
72
68
64
58
78
69
16/20 (56:44)
17/21 (58:42)
18/22 (80:20)
15
19/23 (55:45)
a
Key: (a) MOMCl, DIEA; (b) SOCl2; (c) CH2dCHCH2SH, Et3N;
(d) (i) MeNH2, (ii) HCl; (e) TBSCl, imidazole; (f) toluene, 140-190
°C; (g) toluene, 140 °C.
Sch em e 3
F igu r e 1.
lamine gave the allyl thioether 5, which was transformed
into the pyridone 6 by reaction with methylamine fol-
lowed by acidic workup (58% overall yield). Treatment
of 6 with TBSCl and imidazole provided the pyridone 7
in quantitative yield. Unfortunately, unlike the homolo-
gous pyrone (8), which gives the corresponding cycload-
duct 9a by thermolysis at 140 °C,3 pyridone 7 remained
unchanged after heating in toluene for several hours,
even at 190 °C. Although the mechanism of the thermal
[5C + 2C] pyrone-alkene cycloaddition is unclear, the
fact that the pyridone is much less reactive than the
pyrone is presumably associated with the greater aro-
matic character of the former.8
and N-phenylmaleimide as activated dipolarophile. Un-
der these conditions the dipolarophile was rapidly con-
sumed, but no cycloadducts were detected in the reaction
mixture. We assumed that the disappearance of the
dipolarophile was due to a base-induced side reaction and
tried the weaker base 2,2,6,6-tetramethylpiperidine (TMP).
Satisfyingly, stirring a mixture of the crude pyridinium
salt 12 and N-phenylmaleimide (5 equiv) in refluxing
CH3CN in the presence of 1.5 equiv of TMP for 6 h gave
the exo adduct 14 smoothly in over 72% isolated yield.
The stereochemistry of the adduct was deduced from the
negligibly small coupling constant across the 5,6 posi-
tions.
Since it is known that simple 3-oxidopyridinium ylides
undergo dipolar cycloaddition reactions with a variety of
activated alkenes,7j,9 we reasoned that transformation of
the 3-alkoxy-4-pyridones into 4-methoxy-3-oxidopyri-
dinium ylides might provide a way to accomplish the [5C
+ 2C] cycloaddition.10 The feasibility of this strategy was
initially investigated for intermolecular cases.
The cycloaddition reaction also succeeded with several
asymmetric electron-deficient alkenes, such as acryloni-
trile, methyl acrylate, and phenyl vinyl sulfone, but in
these cases mixtures of exo and endo stereoisomers were
obtained (Table 1, Figure 1). The regio- and stereochem-
ical assignments follow from the chemical shifts and
1
coupling patterns observed in their H NMR spectra. The
Reaction of 3-(benzyloxy)maltol (10b) with MeNH2
afforded the pyridone 11b (Scheme 3), which was readily
converted to the 3-hydroxy-4-pyridone 11a by hydrogena-
tion (78% yield for the two steps).5a The latter compound
can also be prepared directly from maltol (10a ), although
in much lower yield (16%).5c Heating of a solution of 11a
in CHCl3 with 1.5 equiv of MeOTf provided the pyri-
dinium salt 12.11
reaction with phenyl vinyl sulfone is particularly promis-
ing because reductive removal of the sulfone group at
some suitable stage in the azabicycle elaboration would
afford the typical 6,7 unsubstituted tropane system.12
The complete regioselectivity of the reaction can be
easily rationalized on the basis of the frontier molecular
orbital theory.13 Semiempirical calculations predict that
the HOMO of the 4-methoxy-3-oxidopyridinium ylide has
a larger coefficient for position 2 (-0.58) than for position
6 (+0.47).14 Since for electron-deficient alkenes the Câ
coefficient of the LUMO is larger than the CR, the
dominant interaction between the frontier orbitals ac-
Initial attempts to induce the dipolar cycloaddition of
12 were conducted using DBU as ylide-generating base
(8) J ohnson, C. R. in Comprehensive Heterocyclic Chemistry; Ka-
trizky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 2,
Chapter 2.04.
(9) (a) Dennis, N.; Katrizky, A. R.; Takeuchi, Y. Angew. Chem., Int.
Ed. Engl. 1976, 15, 1. For a review of cycloaddition reactions of
heteroaromatic six-membered rings, including oxidopyridinium and
oxidopyrilium systems, see: (b) Katritzky, A. R.; Dennis, N. Chem.
Rev. 1989, 89, 827-861.
(10) This type of transformation has previously been used to convert
the homologous pyrones into pyrilium salts: see ref 2j,k.
(11) This salt can be crystallized from EtOAc or used directly as a
crude reagent in the cycloaddition step.
(12) The reductive removal of the sulfone group has previously been
described for related bicyclic systems: Pandey, G.; Lakshamaiah, G.;
Ghatak, A. Tetrahedron Lett. 1993, 34, 7301.
(13) (a) Katrizky, A.; Dennis, N.; Chaillet, M.; Larrieu, C.; Mouhtadi,
M. E. J . Chem. Soc., Perkin Trans. 1 1979, 408. (b) Hamaguchi, M;
Matsuura, H; Nagai, T. J . Chem. Soc., Chem. Commun. 1982, 263.
(14) Approximate frontier orbital coefficients at the reaction centers
of these pyridinium betaines were calculated by the PM3 method using
the MOPAC program.

6116 J . Org. Chem., Vol. 61, No. 18, 1996
Rumbo et al.
Sch em e 4a
counts for the experimental result. Furthermore, com-
parison of the coefficients at the reactive centers of the
HOMO of our betaine with those of the parent unsub-
stituted 3-oxidopyridinium dipole reveals that the pres-
ence of the 4-methoxy group induces a slight but signifi-
cant increase in their size difference.15 These data may
explain the entire regioselectivity of our reactions in
comparison with that reported for cycloadditions with
4-unsubstituted oxidopyridinium ylides.13
We also evaluated the possibility of using primary
amines other than methylamine to convert the pyrones
into pyridones and, hence, of preparing azabicycles with
different substituents at the nitrogen. This was of
interest not only as an entry to novel tropanes with
modulated biological properties6d but also as a potential
way to introduce asymmetry in the system.16 Reaction
of the 3-(methoxymethyl)maltol derivative 10c with
BnNH2, followed by acidic deprotection, afforded the
3-hydroxy-4-pyridone 11c in 70% yield. Treatment of
this pyridone with MeOTf provided the crude pyridinium
salt 13, which was used directly in cycloaddition reactions
with N-phenylmaleimide and acrylonitrile. The selectiv-
ity and efficiency of these reactions were similar to those
obtained with the N-methyl analog (Table 1).
a
Key: (a) PMBCl, Bu4NI; (b) CH2dCHCH2Br, KF, alumina; (c)
MeNH2; (d) TFA; (e) TBSCl, imid; (f) MeOTf; (g) TMP, CH3CN,
reflux.
pyrone (kojic acid) was transformed in only a few steps
into a tricyclic adduct with a much higher degree of
structural, stereochemical, and functional complexity.20
Con clu sion
Having demonstrated the validity of the methodology
for rapid bimolecular assembly of richly substituted
8-azabicyclo[3.2.1]octenones, we turned our attention to
the intramolecular processes, which would allow the
stereoselective synthesis of an unprecedented type of
fused tropanes.17 The preparation of this type of tropanes
by alternative methods is hampered by the requirement
of running a multistage synthesis for setting up the
appropriate precursors.18
Initial attempts to prepare the pyridinium salt of
pyridone 6 by selective O-4 methylation were thwarted
by the presence of the side chain sulfur atom. We
therefore prepared a cycloaddition precursor bearing an
ether rather than a thioether tether (Scheme 4). Treat-
ment of the (p-methoxybenzyl)kojic acid derivative 25
with allyl bromide and KO-t-Bu produced the ether 26
although in very low yield (15%). However, when the
reaction was carried out with KF adsorbed on alumina,19
the desired ether was obtained in a 92% yield. Reaction
of 26 with methylamine and removal of the protecting
group in an acidic medium gave the expected 3-hydroxy-
4-pyridone 27 in 81% yield.
In contrast to their parent pyrones, 3-alkoxy-4-pyri-
dones fail to undergo direct thermal [5C + 2C] cyclo-
addition to alkenes. The annulation can, however, be
achieved driving the reaction through a dipolar mecha-
nism, by converting the pyridones into 4-methoxy-3-oxi-
dopyridinium ylides. The rich substitution pattern of the
resulting 8-azabicyclo[3.2.1]octane adducts might allow
their divergent conversion to a variety of novel tropane
derivatives. Thus, although 3-hydroxy-4-pyrones have
no obvious structural resemblance to the tropane azabi-
cyclic skeleton, viewing the former as oxidopyridinium
ylide precursors led to a new, practical entry to the sec-
ond. Our current work in this area is focused on the di-
vergent manipulation of the cycloadducts to obtain tro-
pane analogs of potential biological interest and on the
development of asymmetric versions of the cycloaddition.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were conducted in dry
solvents under argon atmosphere unless otherwise stated. The
dry solvents were freshly distilled under argon from the
appropriate drying agent, before use: toluene and THF from
sodium/benzophenone; CH2Cl2, CHCl3, and CCl4 from P2O5,
and CH3CN and Et3N from CaH2. DMF was distilled from
P2O5 under vacuum and stored in the presence of type 4A
molecular sieves. Thin layer chromatography (TLC) was
performed on silica gel plates, and components were visualized
by observation under UV light or by heating the plates after
treatment with a phosphomolybdic reagent. Dryings were
performed with anhydrous Na2SO4. Melting points (open
capillary tubes) are uncorrected.
As in the case of pyridone 7, thermolysis of the silylated
derivative 28 in toluene for several hours at 140-190 °C
failed to give any cycloadduct (mainly affording starting
material), but reflux of a solution of 27 in CHCl3 with
MeOTf, removal of the solvents in vacuo, and treatment
of an acetonitrile solution of the resulting crude with
TMP in a sealed tube at 100 °C provided the desired exo
cycloadduct 29 in 95% yield. Overall, a readily available
1H and 13C NMR spectra were recorded at 250 and 62.83
MHz, respectively, in CDCl3, unless otherwise indicated.
Chemical shifts are reported in ppm (δ). Assignment of the
1H NMR signals of some compounds was based on decoupling
and COSY experiments. Carbon types were determined from
DEPT 13C NMR experiments. The following abbreviations are
used to indicate signal multiplicity: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. Mass spectra were
measured at 70 eV, and relative intensities are given in
parentheses.
(15) Calculations performed with the same method show a coefficient
of -0.53 (C2) and 0.50 (C6) in the HOMO of the 4-unsubstituted
pyridinium salt.
(16) Previous attempts to induce asymmetry in simple oxidopyri-
dinium cycloadditions have been based on the introduction of the chiral
auxiliary in the dipolarophile, which leads to poor stereofacial selectiv-
ity: Takahashi, T; Fujii, A.; Sugita, J .; Hagi, T.; Kitano, K.; Arai, Y.;
Koizume, T. Tetrahedron Asymmetry 1991, 2, 1379.
(17) There is a current interest in the preparation of related fused
tropanes: Davies, H. M. L.; Matasi, J . J .; Ahmed, G. J . Org. Chem.
1996, 61, 2305.
(18) (a) Bromidge, S. M.; Archer, D. A.; Sammes, P. G. Synthesis
1992, 645. (b) Bromidge, S. M.; Archer, D. A.; Sammes, P. G. J . Chem.
Soc., Perkin Trans. 1 1990, 353.
(19) Ando, T.; Yamawaki, J .; Kawate, T.; Sumi, S.; Hanafusa, T.
Bull. Chem. Soc. J pn. 1982, 55, 2504.
(20) Wender, P. A.; Miller, B. L. in Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; J AI Press: New York, 1993; Vol. 2,
pp 27-66.

Entry to Highly Substituted 8-Azabicyclo[3.2.1]octanes
J . Org. Chem., Vol. 61, No. 18, 1996 6117
2-(Ch lor om et h ylen e)-5-[(m et h oxym et h ylen e)oxy]-4-
p yr on e (4). Diisopropylethylamine (8.2 mL, 46.7 mmol) and
methoxymethylene chloride (3.51 mL, 46.7 mmol) were added
to a solution of 2-(chloromethylene)-5-hydroxy-4-pyrone3 (5 g,
31.1 mmol) in CH2Cl2 (50 mL), and the mixture was stirred
for 3 h at room temperature. The reaction mixture was poured
into brine and extracted with CH2Cl2. The combined organic
layers were dried and concentrated. The residue was chro-
matographed (30-70% EtOAc/hexanes) to give 6.24 g of the
pyrone 4 [99%, Rf 0.24 (EtOAc), white solid, mp 63-65 °C]:
1H NMR δ 7.89 (1H, s), 6.44 (1H, s), 5.08 (2H, s), 4.29 (2H, s),
3.44 (3H, s); 13C NMR δ 174.1 (C), 161.7 (C), 146.2 (C), 143.0
(CH), 115.2 (CH), 95.8 (CH2), 56.4 (CH3), 40.8 (CH2); LRMS
m/z 204 (M+, 4), 203 (14), 191 (13), 189 (38), 175 (15), 173 (42),
169 (17), 161 (13), 146 (36), 145 (23), 144 (100), 138 (19), 95
(37), 69 (10), 67 (11), 58 (25); HRMS calcd for C8H9O4Cl
204.018 94, found 204.018 70.
2-[(Allylth io)m eth ylen e]-5-[(m eth oxym eth ylen e)oxy]-
4-p yr on e (5). Triethylamine (5.0 mL, 39.1 mmol) and al-
lylmercaptane (3.2 mL, 39.1 mmol) were added to a solution
of 4 (4 g, 19.5 mmol) in THF (50 mL). The mixture was stirred
for 3 days at room temperature, poured into a saturated
solution of NaHCO3, and extracted with CH2Cl2. The organic
layer was dried and concentrated. The residue was purified
by flash chromatography (30-70% EtOAc/hexanes) to give 3.92
g of the pyrone 5 [83%, Rf 0.51 (50% EtOAc/hexanes), white
solid, mp 48-50 °C]: 1H NMR δ 7.86 (1H, s), 6.30 (1H, s), 5.71
(1H, m), 5.11 (2H, m), 5.09 (2H, s), 3.46 (3H, s), 3.40 (2H, s),
3.12 (2H, d, J ) 6.1 Hz); 13C NMR δ 174.1 (C), 164.5 (C), 145.5
(C), 143.1 (CH2), 132.9 (CH2), 118.3 (CH), 114.2 (CH2), 95.2
(CH), 56.1 (CH3), 34.2 (CH2), 31.3 (CH2); LRMS m/z 242 (M+,
13), 227 (63), 185 (20), 182 (100), 168 (48), 156 (34), 140 (13),
110 (25), 95 (41), 87 (16), 73 9 (11), 69 (24), 53 (16); HRMS
calcd for C11H14O4S 242.061 228, found 242.061 49.
a catalytic amount of DMAP were added to a solution of 6 (200
mg, 0.9 mmol) in CH2Cl2 (10 mL). The mixture was stirred
at room temperature for 30 min, poured into brine, and
extracted with CH2Cl2. The organic layers were dried, filtered,
and concentrated. The residue was chromatographed on
neutral alumina (deactivated with 6% H2O) to afford 280 mg
of 7 [91%, Rf 0.78 (EtOAc), viscous oil]: 1H NMR δ 7.18 (1H,
s), 6.14 (1H, s), 5.66 (1H, m), 5.11 (2H, m), 3.63 (3H, s), 3.59
(2H, s), 3.19 (2H, d, J ) 6.4 Hz), 0.92 (9H, s), 0.18 (6H, s).
3-(Ben zyloxy)-2-m eth yl-4-p yr on e (10b). Potassium hy-
droxide (5.4 g, 95.1 mmol) was added to a solution of 3-hy-
droxy-2-methyl-4-pyrone (8 g, 63.4 mol) in dry MeOH (150 mL).
When the mixture was homogeneous, benzyl bromide (11.6
mL, 95.1 mmol) was added. The reaction mixture was stirred
overnight at room temperature. After evaporation of the
solvent, the crude was poured into brine and extracted with
CH2Cl2. The organic extracts were washed with brine, dried,
filtered, and concentrated. The residue was purified by flash
chromatography (25-75% EtOAc/hexanes) to give 13.55 g of
the pyrone 10b [99%, Rf 0.53 (Et2O), viscous oil]: 1H NMR δ
7.55 (1H, d, J ) 5.7 Hz), 7.33 (5H, m), 6.30 (1H, d, J ) 5.7
Hz), 5.11 (2H, s), 2.04 (3H, s); 13C NMR δ 175.1 (C), 159.7 (C),
153.6 (CH), 143.8 (C), 136.9 (C), 129.0 (CH), 128.4 (CH), 128.3
(CH), 117.1 (CH), 73.5 (CH2), 14.6 (CH3); LRMS m/z 217 (M+,
3.8), 216 (25), 110 (14), 91 (100), 69 (5), 65 (13); HRMS calcd
for C13H12O3 216.078 64, found 216.079 00. Anal. Calcd for
C13H12O3: C, 72.210; H, 5.593. Found: C, 72.19; H, 5.52.
3-(Ben zyloxy)-1,2-d im eth yl-4-p yr id on e (11b). Aqueous
methylamine (40%, 50 mL, 650 mmol) was added to a solution
of 10b (12 g, 55.2 mmol) in absolute EtOH (140 mL). The
mixture was stirred for 22 h at room temperature. The solvent
was evaporated, and the crude was poured into water and
extracted with CH2Cl2 (4 × 200 mL). The organic extracts
were dried, filtered, and concentrated. The residue was
purified by flash chromatography (2-10% MeOH/CH2Cl2) to
give 12.53 g of the pyridone 11b [99%, Rf 0.55 (10% MeOH/
CH2Cl2), viscous oil]: 1H NMR δ 7.27 (5H, m), 7.11 (1H, d, J
) 7.4 Hz), 6.23 (1H, d, J ) 7.5 Hz), 5.10 (2H, s), 3.4 (3H, s),
2.00 (3H, s); 13C NMR δ 173.3 (C), 146.3 (C), 141.2 (C), 139.1
(CH), 137.7 (C), 128.9 (CH), 128.3 (CH), 127.9 (CH), 116.9
(CH), 72.8 (CH2), 41.3 (CH3), 12.7 (CH3); LRMS m/z 230 (M+,
8), 229 (51), 228 (8), 152 (12), 149 (5), 138 (32), 124 (14) 123
(100), 122 (14), 110 (62), 91 (52); HRMS calcd for C14H15O2N
229.110 28, found 229.110 44.
2-[(Allylt h io)m et h ylen e]-5-h yd r oxy-1-m et h yl-4-p yr i-
d on e (6). Aqueous methylamine (40%, 7 mL, 90 mmol) was
added a solution of 5 (3 g, 12.4 mmol) in ethanol (15 mL). The
mixture was stirred overnight at room temperature. The
solvent was evaporated and the resulting residue partitioned
between water and CH2Cl2. The aqueous phases were further
extracted with CH2Cl2 and the combined organic extracts dried
and concentrated. Although the residue (3.2 g) was directly
subjected to the deprotection step, a small amount was purified
by flash chromatography (0-10% MeOH/CH2Cl2) in order to
complete its characterization. The expected product, 2-[(a l-
lylth io)m eth ylen e]-5-[(m eth oxym eth ylen )oxy]-1-m eth yl-
4-p yr id on e, was obtained as a red solid [Rf 0.64 (10% MeOH/
1,2-Dim eth yl-3-h yd r oxy-4-p yr id on e (11a ). Palladium on
activated carbon (1.2 g, 5%) was added to a solution of 11b
(12 g, 52.2 mmol) in MeOH (150 mL), and the mixture was
stirred under H2 for 2 h. The suspension was filtered through
celite and washed with hot MeOH. The solvent was evapo-
rated and the residue chromatographed to give 5.83 g of 11a
[80%, Rf 0.47 (10% MeOH/CH2Cl2), white solid]. The pure
1
CH2Cl2), mp 71-73 °C]: H NMR δ 7.22 (1H, s), 6.14 (1H, s),
5.60 (1H, m), 5.08 (2H, m), 5.02 (2H, s), 3.58 (3H, s), 3.35 (5H,
s), 3.0 (2H, d, J ) 6.9 Hz); 13C NMR δ 172.5 (C), 146.6 (C),
144.6 (C), 133.1 (CH), 130.1 (CH), 118.6 (CH2), 118.6 (CH),
95.6 (CH2), 56.3 (CH3), 40.6 (CH3), 33.5 (CH2), 31.1 (CH2);
LRMS m/z 255 (M+, 10), 254 (44), 241 (14), 240 (100), 212 (11),
198 (13), 195 (52), 182 (29), 170 (69), 153 (41), 150 (20), 139
(38), 124 (21), 110 (32); HRMS calcd for C12H17O3NS 255.092 92,
found 255.092 56.
1
compound was crystallized from MeOH: mp 272-276 °C; H
NMR δ: 7.22 (1H, d, J ) 7.4 Hz), 6.37 (1H, d, J ) 7.3 Hz),
3.65 (3H, s), 2.39 (3H, s); 13C NMR δ 169.7, 146.3, 137.5, 128.3,
110.9, 41.5, 12.1; LRMS m/z 139 (M+, 100), 123 (9), 111(16),
110 (66), 105 (20), 97 (10), 91 (26); HRMS calcd for C7H9O2N
139.063 33, found 139.063 45. Anal. Calcd for C7H9O2N: C,
60.420; H, 6.51; N, 10.006. Found: C, 60.62; H, 6.63; N, 10.10.
1,2-Dim et h yl-3-h yd r oxy-4-m et h oxyp yr id in iu m Tr i-
flu or om eth a n esu lfon a te (12). Freshly distilled methyl
trifluoromethanesulfonate (1.39 g, 8.5 mmol, 960 mL) was
added to a solution of 11a (1.0 g, 7.1 mmol) in CHCl3 (50 mL).
The mixture was refluxed for 3 h and the solvent evaporated
under vacuum. The solid residue was crystallized from EtOAc
to give 1.94 g of the salt 12 [90%, white solid, mp 105-107
°C]: 1H NMR [(CD3)2CO] δ 9.81 (1H, br s), 8.52 (1H, d, J )
7.1 Hz), 7.55 (1H, d, J ) 7.1 Hz), 4.28 (3H, s), 4.18 (3H, s),
2.71 (3H, s); 13C NMR [(CD3)2CO] δ 159.7 (C), 144.7 (C), 143.3
(C), 140.7 (CH), 108.3 (CH), 58.3 (CH3), 45.4 (CH3), 13.1 (CH3).
Anal. Calcd for C9H12O5SNF3: C, 35.46; H, 3.83; N, 4.59.
Found: C, 35.65; H, 3.99; N, 4.62.
A solution of 2 g of the residue obtained from the previous
experiment in THF/H2O (10:1, 22 mL) was stirred with HCl
(10%, 1 mL) for 20 h at room temperature. The mixture was
carefully poured into a saturated solution of NaHCO3 and
extracted with CH2Cl2 (50 × 3) The combined organic layers
were dried and concentrated. The residue was subjected to
flash cromatography (0-10% MeOH/CH2Cl2) to give 1.23 g of
the pyridone 6 [72% from 5, Rf 0.50 (10% MeOH/CH2Cl2), red
solid, mp 98-100 °C]: 1H NMR [(CD3)2SO] δ 7.45 (1H, s), 6.14
(1H, s), 5.77 (1H, m), 5.18 (2H, m), 3.65 (5H, broad s), 3.15
(2H, d, J ) 6 Hz); 13C NMR [(CD3)2SO] δ 170.4 (C), 147.3 (C),
143.9 (C), 134.1 (CH), 125.2 (CH), 117.8 (CH2), 114.4 (CH),
39.5 (CH3), 33.4 (CH2), 31.0 (CH2); LRMS m/z 211 (M+, 19),
139 (25), 138 (77), 111 (10), 110 (100), 71 (8), 67 (11), 58 (25);
HRMS calcd for C10H13O2NS 211.066 70, found 211.066 74.
Anal. Calcd for C10H13O2NS: C, 56.849; H, 6.202; N, 6.630.
Found: C, 56.76; H, 6.75; N, 6.57.
(1R*,5R*,6S*,7S*)-1,8 Dim et h yl-3-m et h oxy-2-oxo-N-
p h e n yl-8-a za b icyclo[3.2.1]oct -3-e n e -6,7-exo-d ica r b ox-
im id e (14). 2,2,6,6-Tetramethylpiperidine (0.16 mL, 0.99
mmol) was added to a solution of 12 (200 mg, 0.66 mmol) and
N-phenylmalemide (570 mg, 3.3 mmol) in CH3CN (10 mL). The
2-[(Allylt h io)m et h ylen e]-5-[(ter t-b u t yld im et h ylsilyl)-
oxy]-1-m eth yl-4-p yr id on e (7). Triethylamine (0.1 mL, 1.4
mmol), tert-butyldimethylsilyl chloride (225 mg, 1.4 mmol), and

6118 J . Org. Chem., Vol. 61, No. 18, 1996
Rumbo et al.
mixture was refluxed for 2 h, poured into water, and extracted
with CH2Cl2. The organic layer was dried and concentrated
and the residue purified by flash chromatography (20-50%
EtOAc/hexanes) to give 154 mg of the cycloadduct 14 [72%, Rf
0.72 (EtOAc), white solid, mp 151-153 °C]: 1H NMR δ 7.36
(5H, m), 5.83 (1H, d, J ) 5.5 Hz), 4.30 (1H, d, J ) 5.5Hz), 3.63
(3H, s), 3.37 (1H, d, J ) 7.4 Hz), 3.02 (1H, d, J ) 7.4 Hz), 2.32
(3H, s), 1.39 (3H, s); 13C NMR δ 193.7 (C), 175.8 (C), 173.6
(C), 150.6 (C), 131.9 (C), 129.2 (CH), 128.8 (CH), 126.4 (CH),
111.2 (CH), 72.3 (C), 61.7 (CH), 55.1 (CH3), 51.8 (CH), 48.5
(CH), 31.5 (CH3), 15.8 (CH3); LRMS m/z 326 (M+, 3), 284 (19),
283 (100), 173 (61), 153 (22), 136 (43), 125 (84), 122 (18), 119
(18), 108 (29), 94 (31), 91 (24), 77 (18), 64 (18), 56 (57), 54 (23),
53 (23); HRMS calcd for C18H18O4N2 326.126 66, found
326.127 12. Anal. Calcd for C18H18O4N2: C, 66.247; H, 5.559;
N, 8.584. Found: C, 65.89; H, 5.75; N, 8.32.
(1R*,5R*,6S*)-6-exo-Cya n o-1,8 d im eth yl-3-m eth oxy-8-
a za bicyclo[3.2.1]oct -3-en -2-on e (16) a n d (1R*,5R*,6R*)-
6-en do-Cyan o-1,8-dim eth yl-3-m eth oxy-8-azabicyclo[3.2.1]-
oct-3-en -2-on e (20). Acrylonitrile (15 mL, 24.6 mmol) was
added to a solution of the oxidopyridinium salt 12 (800 mg,
2.6 mmol) in CH3CN (20 mL). 2,2,6,6-Tetramethylpiperidine
(0.64 mL, 4 mmol) was slowly added, and the mixture was
heated under reflux for 10 h. The reaction mixture was poured
into water and extracted with CH2Cl2. The organic layer was
dried and concentrated and the residue purified by flash
chromatography (25-50% EtOAc/hexanes) to afford 16 (205
mg) and 20 (164 mg) as white solids (68% overall yield). 16
[Rf 0.40 (EtOAc), cryst. Et2O mp 139-141 °C]: 1H NMR δ 5.62
(1H, d, J ) 5.6 Hz), 4.32 (1H, d, J ) 5.6 Hz), 3.59 (3H, s), 2.87
(1H, t, J ) 6.4 Hz), 2.36 (3H, s), 2.24 (2H, d, J ) 6.4 Hz), 1.36
(3H, s); 13C NMR δ 195.4 (C), 151.1 (C), 121.8 (C), 109.1 (CH),
69.8 (C), 64.2 (CH), 55.1 (CH3), 37.6 (CH2), 31.9 (CH), 31.4
(CH3), 17.7 (CH3); LRMS m/z 206 (M+, 5), 178 (43), 163 (100),
152 (12), 148 (20), 147 (30), 135 (25), 125 (26), 106 (23), 94
(19), 56 (56); HRMS calcd for C11H14O2N2 206.105 53, found
206.105 55. Anal. Calcd for C11H14O2N2: C, 64.061; H, 6.842;
N, 13.583. Found: C, 64.126; H, 6.92; N, 13.56. 20 [Rf 0.59
(EtOAc), cryst CH2Cl2/Et2O (1:1) mp 150-152 °C]: 1H NMR δ
5.68 (1H, d, J ) 5.5 Hz), 4.01 (1H, t, J ) 5.5 Hz), 3.57 (3H, s),
3.28 (1H, ddd, J ) 5.5, 6.2, 10.3 Hz), 2.27 (1H, dd, J ) 10.3,
13.9 Hz), 2.19 (3H, s), 1.93 (1H, dd, J ) 6.3, 13.9 Hz), 1.19
(3H, s); 13C NMR δ 195.1 (C), 151.1 (C), 120.0 (C), 108.9 (CH),
70.1 (C), 61.8 (CH), 55.2 (CH3), 37.1 (CH2), 32.2 (CH), 30.6
(CH3), 17.4 (CH3); LRMS m/z 206 (M+, 8), 178 (22), 163 (52),
148 (11), 147 (18), 125 (16), 106 (16), 69 (13), 57 (22), 56 (100).
Anal. Calcd for C11H14O2N2: C, 64.061; H, 6.842; N, 13.583.
Found: C, 63.93; H, 6.95; N, 13.58.
(M+, 15), 211 (36), 196 (58), 180 (12),164 (73), 154 (28), 153
(11), 152 (54), 137 (14), 136 (100), 125 (26), 108 (29), 96 (13),
94 (18), 56 (59), 55 (16); HRMS calcd for C12H17O4N 239.1158,
found 239.11585.
(1R*,5R*,6S*)-1,8-Dim et h yl-3-m et h oxy-6-exo-(p h en yl-
su lfon yl)-8-a za bicyclo[3.2.1]oct-3-en -2-on e (18) a n d (1R*,
5R*,6R*)-1,8-Dim eth yl-3-m eth oxy-6-en do-(ph en ylsu lfon yl)-
8-a za bicyclo[3.2.1]oct-3-en -2-on e (22). 2,2,6,6-Tetramethyl-
piperidine (0.16 mL, 0.99 mmol) was added to a refluxing
solution of 12 (200 mg, 0.66 mmol) and phenyl vinyl sulfone
(570 mg, 3.3 mmol) in CH3CN (6 mL). The mixture was
refluxed overnight, poured into water, and extracted with
CH2Cl2. The organic layer was dried and concentrated and
the residue purified by flash chromatography (20-50% EtOAc/
hexanes) to give 94 mg of compound 18 and 24 mg of 22 (total
yield 58%). 18 [Rf 0.37 (EtOAc), white solid, mp 118-120 °C]:
1H NMR δ 7.89 (2H, m), 7.57 (3H, m), 5.69 (1H, d, J ) 5.3
Hz), 4.33 (1H, d, J ) 5.5 Hz), 3.59 (3H, s), 3.52 (1H, dd, J )
3.8, 9.1 Hz), 2.30 (1H, dd, J ) 3.9, 14.8 Hz), 2.15 (1H, dd, J )
9.1, 14.8 Hz), 2.11 (3H, s), 1.05 (3H, s); 13C NMR δ 195.7 (C),
151.1 (C), 138.0 (C), 133.8 (CH), 129.1 (CH), 128.9 (CH), 109.8
(C), 69.8 (C), 67.3 (CH), 61.2 (CH), 55.1 (CH3), 34.5 (CH2), 30.8
(CH3), 17.3 (CH3); LRMS m/z 321 (M+, 1.3), 278 (19), 152 (47),
137 (14), 136 (100), 125 (27), 108 (35), 96 (11), 94 (18), 82 (14),
77 (50); HRMS calcd for C16H19O4NS 321.10348, found
321.10332. 22 [Rf 0.24 (EtOAc), white solid, mp 107-109 °C]:
1H NMR δ 7.85 (2H, m), 7.57 (3H, m), 5.85 (1H, d, J ) 5.4
Hz), 4.19 (1H, t, J ) 5.3 Hz), 4.05 (1H, ddd, J ) 5.4, 6.9, 9.6
Hz), 3.72 (3H, s), 2.28 (3H, s), 2.25 (1H, dd, J ) 6.9, 13.9 Hz),
2.01 (1H, dd, J ) 9.6, 13.9 Hz), 1.26 (3H, s); 13C NMR δ 195.3
(C), 151.3 (C), 140.1 (C), 133.9 (CH), 129.5 (CH), 127.8 (CH),
108.4 (CH), 70.8 (C), 65.9 (CH), 61.3 (CH), 55.2 (CH3), 34.7
(CH2), 31.6 (CH3), 17.8 (CH3); LRMS m/z 321(M+, 6), 278 (14),
227 (13), 226 (88), 152 (28), 149 (17), 137 (17), 136 (100), 125
(80), 122 (17), 108 (29), 96 (21), 82 (17), 77 (52), 56 (32); HRMS
calcd for C16H19O4NS 321.103 48, found 321.103 33.
3-[(Meth oxym eth ylen e)oxy]-2-m eth yl-4-p yr on e (10c).
Diisopropylethylamine (19 mL, 11.1 mmol) and MOMCl (6 mL,
9.9 mmol) were added to an ice-cooled solution of 10a (7 g,
55.5 mmol). The mixture was stirred overnight at room
temperature, poured into water, and extracted with CH2Cl2.
The organic layer was dried and concentrated, and the residue
was flash chromatographed (30-70% EtOAc/hexanes) to give
8.55 g of the pyrone 10c [94%, Rf 0.38 (EtOAc), viscous oil]:
1H NMR δ 7.61 (1H, d, J ) 5.6 Hz), 6.33 (1H, d, J ) 5.6 Hz),
5.17 (2H, s), 3.52 (3H, s), 2.35 (3H, s); 13C NMR δ 174.4 (C),
159.2 (C), 153.7 (CH), 142.4 (C), 116.7 (CH), 96.9 (CH2), 57.0
(CH3), 14.5 (CH3); LRMS m/z 170 (M+, 2), 155 (23), 139 (26),
127 (130), 110 (100), 109 (15), 82 (10), 71 (11), 69 (34), 53 (19);
HRMS calcd for C8H10O4 170.057 91, found 170.057 83.
1-Ben zyl-3-h yd r oxy-2-m eth yl-4-p yr id on e (11c). Ben-
zylamine (20 mL, 180 mmol) was added to a solution of 10c
(8 g, 47 mmol) in MeOH. The mixture was stirred for 3 days
at room temperature, and more benzylamine (10 mL, 94 mmol)
was added. After 4 days the solvent was evaporated and the
remaining benzylamine removed under high vacuum. The
residue (12.78 g) was directly subjected to the deprotection
step, but a small fraction was purified by flash chromatography
(0-10% MeOH/CH2Cl2) in order to complete its characteriza-
tion. The expected product, 3-[(m eth oxym eth ylen e)oxy]-
1-ben zyl-2-m eth yl-4-p yr id on e, was obtained as a viscous red
oil [98%, Rf 0.58 (EtOAc)]: 1H NMR δ 7.36 (5H, m), 7.03 (1H,
br d, J ) 7.4 Hz), 6.45 (1H, d, J ) 7.5 Hz), 5.29 (2H, s), 5.05
(2H, s), 3.52 (3H, s), 2.34 (3H, s); 13C NMR δ 173.0 (C), 145.3
(C), 141.1 (C), 139.4 (CH), 135.4 (C), 129.2 (CH), 128.3 (CH),
125.9 (CH), 117.1 (CH), 97.2 (CH2), 57.3 (CH2), 56.9 (CH3), 12.6
(CH3); LRMS m/z 259 (M+, 2), 244 (15), 199 (14), 91 (100);
HRMS calcd for C15H17O3N 259.120 84, found 259.120 20.
A solution of 12 g of the residue obtained in the previous
experiment in THF/H2O (10:1, 22 mL) was stirred with HCl
(10%, 1 mL) for 20 h at room temperature. The reaction
mixture was carefully poured into a saturated solution of
NaHCO3 and extracted with CH2Cl2. The organic layer was
dried and concentrated and the residue crystallized from Et2O/
EtOAc (1:1) to afford 7.24 g of 11c [72% from 10c, Rf 0.44 (10%
MeOH/CH2Cl2), white solid, mp 203-205 °C]: 1H NMR [(CD3)2-
(1R*,5R*,6S*)-1,8-Dim eth yl-3-m eth oxy-6-exo-(m eth oxy-
ca r bon yl)-8-a za bicyclo[3.2.1]oct-3-en -2-on e (17) a n d (1R*,
5R*,6R*)-1,8-Dim et h yl-3-m et h oxy-6-en d o-(m et h oxyca r -
bon yl)-8-azabicyclo[3.2.1]oct-3-en -2-on e (21). Methyl acryl-
ate (15 mL, 24.6 mmol) was added to a solution of 12 (800
mg, 2.6 mmol) in CH3CN (20 mL). 2,2,6,6-Tetramethylpip-
eridine (0.64 mL, 4 mmol) was slowly added and the mixture
heated under reflux for 10 h. The reaction mixture was poured
into water and extracted with CH2Cl2. The organic layer was
dried and concentrated and the residue purified by flash
chromatography (25-75% EtOAc/hexanes) to afford the com-
pounds 17 (261 mg) and 21 (142 mg) as white solids, with a
total yield of 64%. 17 [Rf 0.27 (EtOAc), cryst. Et2O mp 101-
102 °C]: 1H NMR δ 5.69 (1H, d, J ) 5.6 Hz), 4.15 (1H, d, J )
5.6 Hz), 3.69 (3H, s), 3.56 (3H, s), 2.79 (1H, dd, J ) 3.4, 9.5
Hz), 2.40 (1H, dd, J ) 3.4, 14.0 Hz), 2.25 (3H, s), 1.97 (1H, dd,
J ) 9.5, 14.0 Hz), 1.26 (3H, s); 13C NMR δ 196.7 (C), 173.4
(C), 150.6 (C), 111.3 (CH), 70.1 (C), 63.2 (CH), 54.8 (CH3), 52.2
(CH3), 46.9 (CH), 35.2 (CH2), 31.9 (CH3); LRMS m/z 239 (M+,
10), 211 (31), 208 (12), 196 (34), 180 (12), 165 (8), 164 (72),
154 (25), 152 (26), 136 (100), 125 (35), 108 (31), 96 (14), 94
(15), 56 (48), 55 (17); HRMS calcd for C12H17O4N 239.1158,
found 239.115 88. 21 [Rf 0.48 (EtOAc), cryst. Et2O mp 92-94
1
°C]: H NMR δ 5.43 (1H, d, J ) 5.5 Hz), 3.92 (1H, t, J ) 5.7
Hz), 3.49 (3H, s), 3.39 (3H, s), 3.34 (1H, m), 2.12 (3H, s), 1.98
(2H, m), 1.12 (3H, s); 13C NMR δ 196.0 (C), 172.1 (C), 151.1
(C), 109.0 (CH), 70.5 (C), 61.8 (CH), 54.9 (CH3), 51.6 (CH3),
46.1 (CH), 34.6 (CH2), 32.1 (CH3), 17.6 (CH3); LRMS m/z 239

Entry to Highly Substituted 8-Azabicyclo[3.2.1]octanes
J . Org. Chem., Vol. 61, No. 18, 1996 6119
SO] δ 7.75 (1H, d, J ) 7 Hz), 7.35 (3H, m), 7.07 (2H, m), 6.21
(1H, d, J ) 7.1 Hz), 5.24 (2H, s), 2.11 (3H, s); 13C NMR δ: 169.4
(C), 146.0 (C), 138.7 (CH), 137.2 (C), 129.1 (CH), 127.8 (CH),
126.2 (CH), 110.9 (CH), 56.1 (CH2), 11.5 (CH3); LRMS m/z 215
(M+, 22), 91 (100), 57 (20); HRMS calcd for C13H13O2N
215.094 63, found 215.094 63. Anal. Calcd for C13H13O2N: C,
72.526; H, 6.091; N, 6.510. Found: C, 72.61; H, 6.16; N,
6.57.
(1R*,5R*,6S*,7S*)-1-Ben zyl-8-m eth yl-3-m eth oxy-2-oxo-
N-p h en yl-8-a za bicyclo[3.2.1]oct-3-en e-6,7-exo-d ica r box-
im id e (15). Freshly distilled methyl trifluoromethane-
sulfonate (0.135 mL, 1.2 mmol) was added to a solution of 11c
(200 mg, 1 mmol) in CHCl3 (50 mL). The mixture was refluxed
for 3 h and the solvent evaporated under vacuum. The crude
residue, a pale yellow solid, was found to consist mainly of
the salt 1-ben zyl-2-m eth yl-3-h yd r oxy-4-m eth oxyp yr id in -
iu m tr iflu or om eth a n esu lfon a te (13) and was used in the
cycloaddition reaction without further purification.
The cycloaddition of 13 to N-phenylmaleimide was carried
out following the same procedure as for the preparation of 14.
Compound 15 (290 mg) was obtained as a white solid in 78%
yield [Rf 0.42 (EtOAc/hexanes), mp 145-147 °C]: 1H NMR δ
7.35 (10H, m), 5.8 (1H, d, J ) 5.7 Hz), 4.21 (1H, d, J ) 5.6
Hz), 3.85 (1H, d, J ) 13.6 Hz), 3.67 (3H, s), 3.63 (1H, d, J )
13.6 Hz), 3.38 (1H, d, J ) 7.3 Hz), 3.12 (1H, d, J ) 7.3 Hz),
1.5 (3H, s); 13C NMR δ 193.2 (C), 175.5 (C), 173.5 (C), 151.1
(C), 137.9 (C), 131.9 (C), 129.3 (CH), 128.9 (CH), 128.7 (CH),
127.8 (CH), 127.6 (CH), 126.4 (CH), 111.7 (CH), 72.4 (C), 57.9
(CH), 55.2 (CH3), 51.4 (CH), 48.8 (CH), 47.8 (CH2), 16.2 (CH3);
LRMS m/z (402, M+, 1), 325 (10), 227 (10), 199 (24), 167 (26),
150 (19), 149 (100), 135 (31), 129 (23), 123 (15), 121 (17), 111
(23), 109 (16), 105 (43); HRMS calcd for C24H22O4N2 402.157 96,
found 402.157 53.
(1R*,5R*,6S*)-6-exo-Cya n o-8-ben zyl-8-m eth yl-3-m eth -
oxy-8-a za bicyclo[3.2.1]oct-3-en -2-on e (19) a n d (1R*,5R*,
6R*)-6-en d o-Cya n o-8-b en zyl-1-m et h yl-3-m et h oxy-8-a za -
bicyclo[3.2.1]oct-3-en -2-on e (23). The cycloaddition of 13
to acrylonitrile was carried out following the same procedure
as for the preparation of 16 and 20. Compounds 19 (91 mg)
and 23 (84 mg) were obtained in 69% global yield. 19 [Rf 0.42
(50% EtOAc/hexanes), viscous oil]: 1H NMR δ 7.28 (5H, m),
5.54 (1H, d, J ) 5.4 Hz), 3.96 (1H, d, J ) 5.4 Hz) 3.86 (1H, d,
J ) 13.9 Hz), 3.54 (1H, d, J )13.9 Hz), 2.85 (1H, dd, J ) 4.8,
7.3 Hz), 2.32 (2H, m), 1.43 (3H, s); 13C NMR δ 195.1 (C), 151.6
(C), 138.1 (C), 128.7 (CH), 128.0 (CH), 127.5 (CH), 121.6 (C),
109.3 (CH), 69.6 (C), 59.9 (CH), 55.2(CH3), 47.9 (CH2), 38.0
(CH2), 31.1 (CH3), 18.1 (CH3); LRMS m/z 282 (M+, 1), 191 (14),
172 (4), 167 (5), 149 (18), 91 (100); HRMS calcd for C17H18O2N2
282.136 83 found 282.136 56. 23 [Rf 0.56 (50% EtOAc/hex-
anes), cryst Et2O, mp 123-125 °C]: 1H NMR δ 7.28 (m, 5H),
5.69 (1H, d, J ) 5.5 Hz), 3.92 (1H, t, J ) 5.5 Hz), 3.75 (1H, d,
J ) 13.2 Hz), 3.72 (3H, s), 3.55 (1H, d, J )13.2 Hz), 3.26 (1H,
ddd, J ) 5.6, 6.4, 10.2 Hz), 2.45 (1H, dd, J ) 10.3, 13.9 Hz),
2.14 (1H, dd, J ) 6.4, 13.9 Hz), 1.41 (3H, s); 13C NMR δ: 194.9
(C), 152.2 (C), 137.9 (C), 128.7 (CH), 128.3 (CH), 127.6 (CH),
119.9 (C), 108.7 (CH), 70.0 (C), 57.6 (CH), 55.4 (CH3), 48.5
(CH2), 37.6 (CH2), 30.6 (CH), 17.9 (CH3); LRMS m/z 282 (M+,
1), 191 (14), 149 (18), 104 (10), 91 (100), 64 (10); HRMS calcd
for C17H18O2N2 282.136 83, found 282.136 74.
168.0 (C), 159.3 (C), 146.6 (C), 141.4 (CH), 129.9 (CH), 128.1
(C), 113.8 (CH), 111.2 (CH), 70.4 (CH2), 59.3 (CH2), 55.0 (CH3);
LRMS m/z 262 (M+, 7), 122 (10), 121 (100); HRMS calcd for
C14H14O5 262.084 12, found 262.084 56. Anal. Calcd for
C14H14O5: C, 64.117; H, 5.380. Found: C, 64.32; H, 5.47.
2-[(Allyloxy)m et h ylen e]-5-[(p -m et h oxyb en zyl)oxy]-4-
p yr on e (26). A potassium fluoride/alumina mixture (40%, 8.3
g, 57.3 mmol) and allyl bromide (20 mL, 22.8 mmol) were
added to a solution of 25 (3 g, 11.4 mmol) in CH3CN (25 mL).
The resulting suspension was refluxed for 22 h and filtered,
and the solids were rinsed with EtOAc. The filtrate was
concentrated and the residue chromatographed (20-40%
EtOAc/hexanes) to give 2.98 g of 26 [86%, Rf 0.43 (50% EtOAc/
1
hexanes), white solid, mp 43-45 °C]: H NMR δ 7.01 (1H, d,
J ) 8.7 Hz), 6.87 (1H, s), 6.51 (1H, d, J ) 8.7 Hz), 6.08 (1H,
s), 5.55 (1H, m), 4.95 (2H, m), 4.67 (2H, s), 3.95 (2H, s), 3.66
(2H, d, J ) 6.9 Hz), 3.43 (3H, s), 3.26 (3H, s); 13C NMR δ: 174.6
(C), 164.0 (C), 159.7 (C), 147.0 (C), 141.7 (CH), 133.5 (CH),
129.6 (CH), 127.8 (C), 118.0 (CH2), 113.9 (CH), 113.4 (CH),
71.95 (CH2), 71.95 (CH2), 71.46 (CH2), 67.4 (CH2), 55.1 (CH3);
LRMS m/z 302 (M+, 4), 151 (4), 121 (100), 95 (4); HRMS calcd
for C17H18O5 302.115 424, found 302.1152. Anal. Calcd for
C17H18O5: C, 67.539; H, 6.001. Found: C, 67.49; H, 5.87.
2-[(Allyloxy)m et h ylen e]-5-h yd r oxy-1-m et h yl-4-p yr i-
d on e (27). Aqueous methylamine (40%, 5 mL, 58 mmol) was
added to a solution of 26 (2.5 g, 8.2 mmol) in EtOH (20 mL).
The mixture was stirred overnight at room temperature and
the solvent removed under reduced pressure. The crude was
partitioned between water and CH2Cl2, and the combined
organic extracts were dried and concentrated. The residue (2.7
g) was directly subjected to the deprotection step, but a small
amount was purified by flash chromatography (0-10% MeOH/
CH2Cl2) in order to characterize the product: 2-[(a llyloxy)-
m et h ylen e]-5-[(p -m et h oxyb en zyl)oxy]-1-m et h yl-4-p yr i-
d on e [Rf 0.72 (10% MeOH/CH2Cl2), red oil]: 1H NMR δ 7.01
(1H, d, J ) 8.7 Hz), 6.87 (1H, s), 6.51 (1H, d, J ) 8.7 Hz), 6.08
(1H, s), 5.55 (1H, m), 4.95 (2H, m), 4.67 (2H, s), 3.95 (2H, s),
3.66 (2H, d, J ) 6.9 Hz), 3.43 (3H, s), 3.26 (3H, s); 13C NMR δ
172.6 (C), 159.3 (C), 147.9 (C), 144.0 (C), 133.4 (CH), 129.4
(CH), 128.8 (C), 117.8 (CH), 117.8 (CH2), 113.6 (CH2), 71.0
(CH2), 70.9 (CH2), 67.8 (CH2), 54.9 (CH3), 40.0 (CH3); LRMS
m/z 315 (M+, 42), 179 (17), 122 (11), 121 (100); HRMS calcd
for C18H21O4N 315.1470 58, found 315.1475 53.
Trifluoroacetic acid (2 mL, 30 mmol) was added to a solution
of part of the residue obtained in the previous experiment (2
g, 6.3 mmol) in CH2Cl2 (18 mL). The mixture was stirred for
6 h at room temperature and the solvent evaporated under
vacuum. The crude was crystallized from CH2Cl2 to give 962
mg of 27 [80% from 26, Rf 0.55 (10% MeOH/CH2Cl2), white
solid, mp 185 °C]: 1H NMR δ 11.09 (1H, br s), 8.25 (1H, s),
7.32 (1H, s), 5.95 (1H, m), 5.22 (2H, m), 4.72 (2H, s), 4.13 (2H,
d, J ) 6.8 Hz), 4.11 (3H, s); 13C NMR δ 164.2 (C), 147.3 (C),
146.6 (C), 135.1 (CH), 133.4 (CH), 118.1 (CH2), 114.4 (CH),
72.4 (CH2), 67.8 (CH2), 43.1 (CH3); LRMS m/z 195 (M+, 61),
153 (10), 139 (55), 138 (29), 111 (14), 110 (100), 69 (28), 67
(13), 55 (10); HRMS calcd for C10H13O3N 195.080 990, found
195.090 201. Anal. Calcd for C14H15O2N: C, 61.510; H, 6.716;
N, 7.178. Found: C, 61.63; H, 6.89; N, 7.21.
2-[(Allyloxy)m et h ylen e]-5-[(ter t-b u t yld im et h ylsilyl)-
oxy]-1-m eth yl-4-p yr id on e (28). To a solution of 6 (200 mg,
1 mmol) in CH2Cl2 (10 mL) were added Et3N (108 µl, 1.5
mmol), t-butyldimethylsilyl chloride (240 mg, 1.5 mmol), and
a catalytic amount of DMAP. The mixture was stirred at room
temperature for 30 min, poured into brine, and extracted with
CH2Cl2. The organic layers were dried, filtered, and concen-
trated. The residue was chromatographed on neutral alumina
(deactivated with 6% H2O) to afford 292 mg of 28 [93%, Rf
0.78 (EtOAc), viscous oil]: 1H NMR δ 7.27 (1H, s), 6.5 (1H, s),
5.97 (1H, m), 5.28 (2H, m), 4.78 (2H, s), 4.23 (2H, d, J ) 6.4
Hz), 4.2 (3H, s), 0.89 (9H, s), 0.24 (6H, s).
2-(H yd r oxym et h ylen e)-5-[(p -m et h oxyb en zyl)oxy]-4-
p yr on e (25). Potassium hydroxide (3.47 g, 61.9 mmol) was
added to a solution of kojic acid (8 g, 56.3 mmol) in water (50
mL). The mixture was stirred until all the kojic acid had
dissolved. The solvent was removed under vacuum to give 10.1
g of crude potassium kojate. Tetrabutylammonium iodide
(24.5 g, 66.6 mmol) and p-methoxybenzyl chloride (9 mL, 66.6
mmol) were added to a suspension of the potassium kojate (8
g, 44.4 mmol) in acetone (150 mL). The mixture was heated
under reflux for 18 h, cooled at room temperature, poured into
water, and extracted with CH2Cl2. The organic extracts were
dried and concentrated. The residue was purified by flash
chromatography (0-5% MeOH/CH2Cl2) to afford 11.4 g of 25
[98%, Rf 0.39 (EtOAc), white solid, cryst MeOH mp 119-121
°C]: 1H NMR δ 8.12 (1H, s), 7.32 (2H, d, J ) 8.2 Hz), 6.93 (2H,
d, J ) 8.2 Hz), 6.31 (1H, s), 5.67 (1H, t, J ) 5.7 Hz), 4.84 (2H,
s), 4.28 (2H, d, J ) 5.4 Hz), 3.74 (3H, s); 13C NMR δ 173.4 (C),
9-Meth oxy-11-m eth yl-8-oxo-11-a za tr icyclo[5.3.1.01,5]u n -
d ec-9-en e (29). Methyl trifluoromethansulfonate (0.135 µL,
1.2 mmol) was added to a solution of 27 (200 mg, 1 mmol) in
CHCl3 (25 mL). The mixture was refluxed for 3 h and
concentrated, and the residue was dried under high vacuum
for 5 h. 2,2,6,6-Tetramethylpiperidine (0.260 mL, 1.5 mmol)

6120 J . Org. Chem., Vol. 61, No. 18, 1996
Rumbo et al.
was added to a solution of this crude salt (378 mg) in CH3CN
(60 mL), and the mixture was heated in a sealed tube at 110
°C overnight. The solvent was evaporated and the residue
chromatographed on silica gel (50-100% EtOAc/hexanes) to
afford 197 mg of the cycloadduct 29 [92% Rf (EtOAc), white
solid, mp 86-89 °C]: 1H NMR [(CD3)2CO] δ 5.9 (1H, s), 4.07
(1H, t, J ) 8 Hz), 3.88 (2H, dd, J ) 15.4 Hz), 3.61 (2H, m),
3.57 (3H, s), 2.76 (1H, ddd, J ) 14.2, 8.6, 5.3 Hz), 2.27 (3H, s),
2.07 (1H, m), 1.55 (1H, dd, J ) 13.3, 8.6 Hz); 13C NMR [(CD3)2-
CO] δ 194.8(C), 153.0 (C), 113.8 (CH), 75.6 (CH), 75.3 (C), 75.1
(CH2), 73.4 (CH2), 55.2 (CH3), 53.4 (CH3), 31.7 (CH3), 28.0
(CH2); LRMS m/z 209 (M+, 47), 181 (39), 167 (12), 166 (100),
150 (63), 138 (30), 109 (46); HRMS calcd for C11H15O3N
209.105 19, found 209.105 19.
Ack n ow led gm en t. We thank the DGICYT (Spain)
and the Xunta de Galicia for financial support under
projects SAF 92-0572, SAF 95-0878, and XUGA
20901A94. A.R. also thanks the Xunta de Galicia for a
fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for 4-6, 11c, 12, 14-23, 26, 27, and 29 (19
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O960854V