Synthesis of substituted pyridines via regiocontrolled [4 + 2] cycloadditions of oximinosulfonates

Article abstract of DOI:10.1021/jo981014e

Diels-Alder cycloadditions of oximinosulfonate 8 with a variety of 1, 3-dienes proceed with regiochemistry opposite to that observed with conventional imino dienophiles, providing expeditious synthetic routes to substituted pyridines, tetrahydropyridines, and pyrrolines. The oximinosulfonate 8 is prepared in one convenient synthetic operation from Meldrum's acid and reacts with conjugated dienes at -78 C in the presence of 2 equiv of dimethylaluminum chloride to afford [4 + 2] cycloadducts in good to excellent yield. Exposure of these cycloadducts to the action of NaOMe and JV-chlorosuccinimide in methanol-THF at room temperature then produces substituted pyridines. The utility of this new two-step annulation protocol is demonstrated in total syntheses of the pyridine alkaloids fusaric acid and (S)-(+)-fusarinolic acid. Heating the [4 + 2] cycloadducts derived from 8 in a mixture of acetonitrile and pH 7 phosphate buffer induces an unusual Stieglitztype rearrangement leading to the formation of interesting spirobicyclic pyrrolines.

Full text of DOI:10.1021/jo981014e

7840
J . Org. Chem. 1998, 63, 7840-7850
Syn th esis of Su bstitu ted P yr id in es via Regiocon tr olled [4 + 2]
Cycloa d d ition s of Oxim in osu lfon a tes
Adam R. Renslo and Rick L. Danheiser*
Department of Chemistry Massachusetts Institute of Technology Cambridge, Massachusetts 02139
Received May 28, 1998
Diels-Alder cycloadditions of oximinosulfonate 8 with a variety of 1,3-dienes proceed with
regiochemistry opposite to that observed with conventional imino dienophiles, providing expeditious
synthetic routes to substituted pyridines, tetrahydropyridines, and pyrrolines. The oximinosulfonate
8 is prepared in one convenient synthetic operation from Meldrum’s acid and reacts with conjugated
dienes at -78 °C in the presence of 2 equiv of dimethylaluminum chloride to afford [4 + 2]
cycloadducts in good to excellent yield. Exposure of these cycloadducts to the action of NaOMe
and N-chlorosuccinimide in methanol-THF at room temperature then produces substituted
pyridines. The utility of this new two-step annulation protocol is demonstrated in total syntheses
of the pyridine alkaloids fusaric acid and (S)-(+)-fusarinolic acid. Heating the [4 + 2] cycloadducts
derived from 8 in a mixture of acetonitrile and pH 7 phosphate buffer induces an unusual Stieglitz-
type rearrangement leading to the formation of interesting spirobicyclic pyrrolines.
In connection with our investigations of [4 + 2]
esters and nitriles during the 1970s. Most useful among
the compounds examined was the bis-nitrile 4, which
reacts with cyclopentadiene3b and a number of acyclic
dienes3d in generally good yield. Unfortunately, these
cycloadditions appear to proceed with poor regioselectiv-
ity (eq 2), and the scope of this chemistry is further
limited by the instability of 4 above 90 °C and the
apparent need to use excess diene in these reactions. A
useful feature of the resulting cycloadducts, however, is
that they undergo aromatization to form pyridines in
good yield simply upon heating in ethanol.3d
cycloadditions of conjugated enynes,1 we became inter-
ested in activated imine derivatives with the ability to
function as reactive 2π components in these and related
cycloadditions. Of particular interest have been systems
such as 1 (eq 1), which we envisioned might be available
via the transition-metal-mediated coupling of an orga-
nometallic species 2 (Met ) Cu, Zn, B, Sn, etc.) with a
readily available oxime building block of type 3 (X ) Ts,
Tf, etc.). Oxime derivatives of type 3 are themselves of
some interest as cycloaddition partners, and we report
herein our studies of the scope of the intermolecular [4
+ 2] cycloadditions of one class of such compounds,
oximinosulfonates derived from Meldrum’s acid. We
have found that cycloadditions of these species proceed
with regiochemistry opposite to that observed with
conventional imino dienophiles,2 providing expeditious
synthetic routes to substituted pyridines, tetrahydropy-
ridines, and pyrrolines.
In related studies, Breitmaier has reported cycloaddi-
tions of oximinosulfonate 4 with oxygenated dienes and
conversion of the cycloadducts to pyridines, albeit in low
yield.4 More recently, Katagiri and co-workers studied
the reaction of the Meldrum’s acid-derived oximinoac-
etate 6 with cyclopentadiene and 2,3-substituted buta-
dienes, finding that most of these cycloadditions require
the application of high-pressure techniques (eq 3).5 Cy-
cloadditions involving unsymmetrical dienes were not
investigated in this study. The modest Diels-Alder
reactivity of dienophile 6 stands in contrast to the related,
unreactive diesters investigated by Fleury3b (i.e., 3, W )
CO2Et, X ) Ts, Ms), which fail to combine with even the
most reactive dienes such as cyclopentadiene. Greater
In contrast to imines, the application of oxime deriva-
tives as dienophiles for the Diels-Alder reaction has
attracted relatively little attention. Most of the work in
this area has been reported by Fleury,3 who described
the synthesis and cycloadditions of a variety of oximino
(1) Danheiser, R. L.; Gould, A. E.; Ferna´ndez de la Pradilla, R.;
Helgason, A. L. J . Org. Chem. 1994, 59, 5514.
(2) For reviews of azadienophiles in the Diels-Alder reaction, see:
(a) Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 401-413.
(b) Weinreb, S. M.; Levin, J . I. Heterocycles 1979, 12, 949. (c) Weinreb,
S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087. (d) Boger, D. L.;
Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic: San Diego, 1987; Chapter 2.
(3) (a) Biehler, J .-M.; Perchais, J .; Fleury, J .-P. Bull. Soc. Chim. Fr.
1971, 2711. (b) Biehler, J .-M.; Fleury, J .-P. J . Heterocycl. Chem. 1971,
8, 431. (c) Perchais, J .; Fleury, J .-P. Tetrahedron 1972, 28, 2267. (d)
Fleury, J .-P.; Desbois, M.; See, J . Bull. Soc. Chim. Fr. 1978, II-147.
(4) Dormagen, W.; Rotscheidt, K.; Breitmaier, E. Synthesis 1988,
636.
(5) Katagiri, N.; Nochi, H.; Kurimoto, A.; Sato, H.; Kaneko, C. Chem.
Pharm. Bull. 1994, 42, 1251.
(6) For reviews of the chemistry of Meldrum’s acid and its deriva-
tives see: (a) McNab, H. Chem. Soc. Rev. 1978, 7, 345. (b) Chen, B.-C.
Heterocycles 1991, 32, 529.
10.1021/jo981014e CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/06/1998

Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates
J . Org. Chem., Vol. 63, No. 22, 1998 7841
orbital overlap between the carbonyl groups and the
oximino π-bond in the cyclic Meldrum’s acid6 derivative
leads to enhanced dienophilicity in 6 relative to the
related acyclic diesters.
synthesis of pyridines. Heteroaromatic azadienes em-
ployed in pyridine synthesis include oxazoles, triazenes,
and diazenes,10 and recently Boger11 and Ghosez12 have
developed methods based on acyclic azadienes which have
been applied in elegant total syntheses of natural prod-
ucts.13 Although a variety of azadienophiles2 have been
used for the synthesis of tetrahydropyridines, few ex-
amples of their application in the synthesis of pyridines
have previously been reported.
Our investigation of the previously unknown oximino-
sulfonate 8 was founded on the expectation that the
Diels-Alder reactions of this system would enjoy several
advantages over the previously reported oximino dieno-
philes 4 and 6 (vide infra). Most importantly, we
anticipated that cycloadditions involving 8 would be
subject to Lewis acid promotion, thus permitting highly
regioselective cycloadditions with an expanded range of
diene substrates under relatively mild reaction condi-
tions. The expectation that cycloadducts of 8 could be
transformed to pyridines in a single synthetic operation
also made this system an attractive candidate for our
investigation.
In this article we report on Diels-Alder reactions of
the previously unknown oximinosulfonate 8 and the facile
transformation of the resulting cycloadducts to pyridines.
Overall, this process provides a valuable regiocontrolled
[4 + 2] annulation strategy for the synthesis of substi-
tuted pyridines, one of the most important classes of
Resu lts a n d Discu ssion
P r ep a r a tion of Oxim in osu lfon a te 8. We have
developed a convenient one-pot procedure for the prepa-
ration of oximinosulfonate 8 (eq 4). Nitrosation of
Meldrum’s acid (9) with 1.0 equiv of sodium nitrite in
methanol-water proceeds smoothly at room tempera-
ture14 to afford an oxime which is sulfonylated in the
same flask by neutralization15 of the solution with pH 7
phosphate buffer followed by addition of tosyl chloride
(0.9 equiv) at 0 °C. The solid oximinosulfonate 8 pre-
cipitates almost immediately, and is collected by filtra-
aromatic nitrogen heterocycles.7 The structures of a
number of natural products8 incorporate the pyridine ring
system, as do important commercial compounds including
herbicides, insecticides, fungicides, and a variety of
medicinal agents.7b Pyridine-metal complexes7c find an
important place in coordination chemistry, and recently
the pyridine ring system has figured prominently in the
design of molecules with important roles in supramo-
lecular chemistry.9 The development of improved syn-
thetic routes to pyridines consequently continues to be a
problem of great interest.7d Pyridine syntheses based on
the Diels-Alder reaction are especially powerful, as their
intrinsic convergent nature often permits the rapid
assembly of complex substituted systems. Both aza-
dienes and azadienophiles have found application in the
tion, washed with cold methanol, and dried in a desic-
cator over P2O5. This simple procedure provides multi-
gram quantities of 8 in high purity as an easily handled
white solid (mp 155-156 °C) which can be transferred
in air and is stable for months when stored under argon
in a refrigerator.
(7) For general reviews of the synthesis and chemistry of pyridines,
see: (a) Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry;
Boulton, A. J ., McKillop, A., Eds.; Pergamon: Oxford, 1984; Vol. 2,
Part 2A, pp 165-314. (b) Yates, F. S. In Comprehensive Heterocyclic
Chemistry; Boulton, A. J ., McKillop, A., Eds.; Pergamon: Oxford, 1984;
Vol. 2, Part 2A, pp 511-524. (c) Tomasik, P.; Ratajewicz, Z. In Pyridine-
Metal Complexes; Newkome, G. R., Strekowski, L., Eds.; The Chemistry
of Heterocyclic Compounds; Wiley: New York, 1985; Vol. 14, Part 6A.
(d) J ones, G. In Comprehensive Heterocyclic Chemistry; Boulton, A. J .;
McKillop, A., Eds.; Pergamon: Oxford, 1984; Vol. 2, Part 2A, pp 395-
510. (e) Pyridine and its Derivatives; Newkome, G. R., Ed; The
Chemistry of Heterocyclic Compounds; Wiley: New York, 1984; Vol.
14, Part 5.
(8) (a) Enzell, C. R.; Wahlberg, I. In Progress in the Chemistry of
Organic Natural Products; Herz, W.; Grisebach, H.; Kirby, G. W., Eds.;
Springer-Verlag: New York, 1977; Vol. 34, p 1. (b) Birkinshaw, J . H.;
Stickings, C. E. In Progress in the Chemistry of Organic Natural
Products; Zechmeister, L., Ed.; Springer-Verlag: Vienna, 1962; Vol.
20, p 1. (c) Cordell, G. A. Introduction to Alkaloids; Wiley: New York,
1981; Chapters 3 and 5.
(9) For reviews see: (a) Chambron, J .-C.; Dietrich-Buchecker, C.;
Sauvage, J .-P. In Comprehensive Supramolecular Chemistry; Sauvage,
J .-P., Hosseini, M. W., Eds.; Pergamon: New York, 1996; Vol. 9, pp
43-84. (b) Amabilino, D. B.; Raymo, F. M.; Stoddart, J . F. In
Comprehensive Supramolecular Chemistry; Sauvage, J .-P., Hosseini,
M. W., Eds.; Pergamon: New York, 1996; Vol. 9, pp 85-130. (c) Baxter,
P. N. W. In Comprehensive Supramolecular Chemistry; Sauvage, J .-
P., Hosseini; M. W., Eds.; Pergamon: New York, 1996; Vol. 9, pp 165-
212.
Th er m a l [4 + 2] Cycloa d d ition s. As anticipated,
oximinosulfonate 8 exhibits dienophilicity in thermal
(11) (a) Boger, D. L.; Curran, T. T. J . Org. Chem. 1990, 55, 5439.
(b) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J . Am.
Chem. Soc. 1991, 113, 1713. (c) Boger, D. L.; Corbett, W. L. J . Org.
Chem. 1993, 58, 2068.
(12) (a) Demoulin, A.; Gorissen, H.; Hesbain-Frisque, A.-M.; Ghosez,
L. J . Am. Chem. Soc. 1975, 97, 4409. (b) Sainte, F.; Serckx-Poncin, B.;
Hesbain-Frisque, A.-M.; Ghosez, L. J . Am. Chem. Soc. 1982, 104, 1428.
(c) Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez, L. Tetrahedron
Lett. 1982, 23, 3261. (d) Bayard, P.; Ghosez, L. Tetrahedron Lett. 1988,
29, 6115.
(13) (a) Boger, D. L.; Nakahara, S. J . Org. Chem. 1991, 56, 880. (b)
Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110, 4051. (c)
Waldner, A. Synth. Commun. 1989, 19, 2371.
(14) Meldrum’s acid is itself sufficiently acidic to catalyze the
nitrosation reaction. For the first report of the nitrosation of Meldrum’s
acid, see: Eistert, B.; Geiss, F. Chem. Ber. 1961, 94, 929.
(15) Neutralization before the addition of TsCl helps prevent the
acid-promoted addition of methanol to 8 (the product is obtained in
35% yield if buffer is not used).
(10) (a) Boger, D. L. Chem. Rev. 1986, 86, 781. (b) Boger, D. L. Bull.
Soc. Chim. Belg. 1990, 99, 599.

7842 J . Org. Chem., Vol. 63, No. 22, 1998
Renslo and Danheiser
Sch em e 1
Diels-Alder reactions comparable to Fleury’s bis-nitrile
4, and considerably greater than that of the correspond-
ing diesters and the oximinoacetate 6. Thus, reaction of
8 with penta-1,3-diene in refluxing benzene produced the
expected cycloadduct 10 (eq 5), the regiochemical assign-
ment for which is based on the observation of a methylene
resonance at 4.04 ppm (CH2N) and a methine resonance
1
at 3.31 ppm (CH(CH3)) in the H NMR spectrum. The
more reactive 2-(triisopropylsiloxy)buta-1,3-diene reacts
similarly at only 55-65 °C to provide cycloadduct 11 in
46-56% yield. Noteworthy is the regiochemical outcome
of these Diels-Alder reactions, in which the carbonyl
substituents direct the cycloaddition to generate products
with regiochemistry opposite to that which would be
observed with conventional imino dienophiles.2
to 8 established the requirement that a full 2.0 equiv of
the Lewis acid is necessary for these reactions. It is likely
that the second equivalent of Me2AlCl serves to promote
ionization of chloride from an initial 1:1 Lewis acid-8
complex, thereby generating the more reactive ionic 2:1
complex 14. This type of Lewis acid behavior has
previously been noted by Lehmkuhl and Kobs,16 and more
recently has been observed by Evans in Diels-Alder
reactions of oxazolidinone-metal complexes such as 15.17
Lew is Acid -P r om oted Cycloa d d ition s. When a
purified sample of cycloadduct 10 was heated at reflux
in benzene, a number of new compounds were produced
and a brown tar formed on the inside of the reaction flask.
This observation suggests that the modest yield obtained
in the reaction of 8 with penta-1,3-diene is due, at least
in part, to the instability of the cycloadduct at elevated
temperature. Consequently, we next turned our atten-
tion to the promotion of cycloadditions of 8 using Lewis
acids, and after some experimentation, we were pleased
to find that Me2AlCl is quite effective at promoting the
desired [4 + 2] cycloaddition. Thus, as outlined in eq 6,
reaction of oximinosulfonate 8 with isoprene or penta-
1,3-diene (3.0 equiv) and Me2AlCl (2.0 equiv) in dichlo-
romethane at -78 °C for 4 h provided the desired
cycloadducts 12 and 13 in high yield and in each case as
a single regioisomer. Once again, the cycloaddition of 8
produces heterocycles with substitution patterns that
cannot be accessed using standard imino Diels-Alder
Syn th esis of Su bstitu ted P yr id in es. Encouraged
by the efficiency and regioselectivity of these cycloaddi-
tions, we next turned our attention to their application
in the context of a regiocontrolled synthesis of substituted
pyridines. Initially, we set as our goal the identification
of conditions for the conversion of the tetrahydropyridine
cycloadducts (17) to pyridines in a single synthetic
operation. It was our expectation that the desired
transformation might be achieved through the simulta-
neous action of a nucleophilic alkoxide reagent and
suitable oxidizing agent on the cycloadducts 17. After
having little success with oxidants such as DDQ, O2, and
air, we ultimately found that the combination of N-
chlorosuccinimide (NCS) and sodium methoxide is espe-
cially effective at bringing about the desired transfor-
mation.18 Thus, treatment of a cooled (0 °C) solution of
17 in methanol-THF (1:1) with 3.0 equiv of NaOMe and
1.0 equiv of NCS, followed by stirring overnight at room
temperature, affords the desired pyridines in generally
excellent yield after chromatographic purification19
(Scheme 1). The mechanism of this multistage reaction
presumably involves initial cleavage of the dioxandione
ring by methoxide with concomitant elimination of
acetone and carbon dioxide. â-Elimination of tosylate
from the resulting ester enolate then generates a dihy-
dropyridine, and subsequent chlorination by NCS and
elimination of HCl finally provides the desired aromatic
product. Optimal yields are obtained by converting the
cycloadducts 17 directly to pyridines without purification,
methodology. Also significant is our finding that Lewis
acids fail to promote cycloadditions involving Fleury’s bis-
nitrile oximinosulfonate 4 and the Meldrum’s acid-
derived oximinoacetate 6 described by Katagiri. In both
cases we observed only decomposition when these dieno-
philes were exposed to Me2AlCl and other Lewis acids
under conditions that lead to successful cycloadditions
with oximinosulfonate 8.
Other reagents such as TiCl4, ZnCl2, AlCl3, methane-
sulfonic acid, and camphorsulfonic acid proved less
effective than Me2AlCl in promoting the desired cycload-
dition; in most cases either decomposition of the starting
materials or no significant rate enhancement was ob-
served. A series of experiments in which Me2AlCl
stoichiometry was varied from 0.1 to 2.5 equiv relative
(16) Lehmkuhl, H.; Kobs, H.-D. Liebigs. Ann. Chem. 1968, 719, 11.
(17) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238.
(18) NCS in conjunction with NaOMe has recently been used for
the oxidation of tetrahydropyridines to pyridines: De Kimpe, N.;
Keppens, M.; Fonck, G. Chem. Commun. 1996, 635.
(19) Care must be exercised to avoid strongly basic workup condi-
tions since the pyridine esters are sensitive to hydrolysis. This difficulty
was circumvented by performing a neutral workup with pH 7 phos-
phate buffer.

Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates
Ta ble 1. [4 + 2] P yr id in e An n u la tion sa
J . Org. Chem., Vol. 63, No. 22, 1998 7843
23 in good yield demonstrates the compatibility of alkene
functionality with the cycloaddition and chlorination
conditions. Structural assignments for the pyridine
annulation products are based on NMR spectroscopic
analyses, and data for the known pyridines 19,20 20,21
2222, and 2423 are fully consistent with that previously
reported for these compounds.
Tot a l Syn t h esis of F u sa r ic Acid a n d (S)-(+)-
F u sa r in olic Acid . The [4 + 2] pyridine annulation
described herein provides a particularly powerful method
for the construction of 5-alkylpicolinic acid derivatives,
an important class of biologically active alkaloids. The
following syntheses of fusaric acid (32) and (S)-(+)-
fusarinolic acid (36) illustrate the utility of the new
annulation strategy as applied to this class of naturally
occurring pyridines.
The phytotoxin fusaric acid is produced by several
species of plant-pathogenic fungi belonging to the genus
Fusarium.24 In nature, fusaric acid acts as a plant
growth inhibitor causing leaf and stem necrosis and
inhibiting root elongation. It has recently been suggested
that fusaric acid might have utility as a herbicide for the
control of the parasitic weed Striga hermonthica (witch-
weed).24h Fusaric acid is also a potent inhibitior25 of
dopamine â-hydroxylase and possesses significant hy-
potensive activity in mammals.24c,e In comparison to
fusaric acid, much less is known about the oxygenated
derivative (S)-(+)-fusarinolic acid (36). This alkaloid was
isolated from Gibberella fujikuroi26 (the same species of
fungus from which fusaric and dehydrofusaric acid had
previously been extracted24b) and displays much lower
phytotoxicity than fusaric acid in tomato plant assays.26
Several syntheses of fusaric acid (32) and (S)-(+)-fusarin-
olic acid (36) have previously been reported,26-28 including
two which involve strategies based on hetero Diels-Alder
reactions of azadiene derivatives.27e,f Despite the rather
simple structure of these alkaloids, most of the reported
routes require five to ten synthetic steps. The application
of an azadienophile-based hetero Diels-Alder strategy
to the synthesis of these natural products has not
previously been reported.
(20) Deady, L. W.; Harrison, P. M.; Topsom, R. D. Org. Magn. Reson.
1975, 7, 41.
(21) Capasso, R.; Evidente, A.; Cutignano, A.; Vurro, M.; Zonno, M.
C.; Bottalico, A. Phytochemistry 1996, 41, 1035.
(22) (a) Hromatka, O.; Binder, D.; Stanetty, P.; Marischler, G.
Monatsh. Chem. 1976, 107, 233. (b) Subramanyam, C.; Chattarjee, S.;
Mallamo, J . P. Tetrahedron Lett. 1996, 37, 459.
(23) Blank, B.; DiTullio, N. W.; Krog, A. J .; Saunders: H. L. J . Med.
Chem. 1979, 22, 840.
a
Conditions: (a) 8, 2.0 equiv of Me2AlCl, CH2Cl2, -78 °C, 2-4
h; (b) 3.0 equiv MeONa, 1.0 equiv of NCS, MeOH-THF (1:1), rt,
14-16 h. 1.5-3.0 equiv of diene was employed. c Isolated overall
b
d
yield for two steps. 5.0 equiv of NaOMe and 4.0 equiv of NCS
were used.
(24) (a) Yabuta, T.; Kambe, K.; Hayashi, T. J . Agric. Chem. Soc.
J pn. 1934, 10, 1059. (b) Grove, J . F.; J effs, P. W.; Mulholland, T. P. C.
J . Chem. Soc. 1958, 1236. (c) Hidaka, H.; Nagatsu, T.; Takeya, K. J .
Antibiot. 1969, 22, 228. (d) Nagatsu, T.; Hidaka, H.; Kuzuya, H.;
Takeya, K.; Umezawa, H.; Takeuchi, T.; Suda, H. Biochem. Pharmacol.
1970, 19, 35. (e) Suda, H.; Takeuchi, T.; Nagatsu, T.; Matsuzaki, M.;
Matsumoto, I.; Umezawa, H. Chem. Pharm. Bull. 1969, 17, 2377. (f)
Claydon, N.; Grove, J . F.; Pople, M. Phytochemistry 1977, 16, 603. (g)
Abraham, W.-R.; Hanssen, H.-P. Tetrahedron 1992, 48, 10559. (h)
Capasso, R.; Evidente, A.; Cutignano, A.; Vurro, M.; Zonno, M. C.;
Bottalico, A. Phytochemistry 1996, 41, 1035.
especially in the case of tetrahydropyridines that are
prone to undergo rearrangement upon purification (vide
infra). Overall, this two-stage protocol comprises a new
regiocontrolled [4 + 2] annulation strategy for the
synthesis of substituted pyridines from 1,3-dienes.
Table 1 delineates the scope of the [4 + 2] pyridine
annulation. A variety of monosubstituted dienes par-
ticipate in the reaction, with the exception of (Z)-dienes,
which as usual do not undergo efficient Diels-Alder
cycloaddition. Reactions involving disubstituted 1,3-
dienes provide convenient access to trisubstituted py-
ridines, although in some cases (e.g., entries 7 and 8)
lower yields are obtained due to competing Stieglitz-type
rearrangement processes (vide infra). Cycloadducts de-
rived from 2,3-disubstituted dienes are particularly prone
to this rearrangement and cannot be employed in the
pyridine annulation. Finally, the preparation of pyridine
(25) Fusaric acid is a nanomolar inhibitor of dopamine â-hydroxylase
(IC50 ) 3.0 × 10-8 M), see: ref 24d.
(26) Steiner, K.; Graf, U.; Hardegger, E. Helv. Chim. Acta 1971, 54,
845.
(27) (a) Plattner, Pl. A.; Keller, W.; Boller, A. Helv. Chim. Acta 1954,
37, 1379. (b) Hardegger, E.; Nikles, E. Helv. Chim. Acta 1957, 40, 1016.
(c) Vogt, H.; Mayer, H. Tetrahedron Lett. 1966, 5887. (d) Tschesche,
R.; Fu¨hrer, W. Chem. Ber. 1978, 111, 3502. (e) Sagi, M.; Amano, M.;
Konno, S.; Yamanaka, H. Heterocycles 1989, 29, 2249. (f) Waldner, A.
Synth. Commun. 1989, 19, 2371. (g) Langhals, E.; Langhals, H.;
Ru¨chardt, C. Liebigs Ann. Chem. 1982, 930.
(28) Bu¨yu¨k, G.; Hardegger, E. Helv. Chim. Acta 1975, 58, 682.

7844 J . Org. Chem., Vol. 63, No. 22, 1998
Renslo and Danheiser
Sch em e 2
Sch em e 4
Sch em e 3
overall yield following chromatographic purification. Un-
reacted diene 31 could be recovered in essentially quan-
titative yield from this reaction. Desilylation of 33 with
tetrabutylammonium fluoride next gave (S)-(+)-methyl
fusarinolate (34) in 94% yield. Analysis of the Mosher
1
ester (35) derived from 34 by H and 19F NMR revealed
only one diastereomer within the detection limits of the
spectrometer.31 The synthesis of (S)-(+)-fusarinolic acid
was then completed by hydrolysis of methyl ester 34 with
KOH in aqueous methanol.32 Attempted crystallization
(dichloromethane-methanol) of the crude product gave
an oil which subsequently crystallized, providing syn-
thetic (S)-(+)-fusarinolic acid in 82% yield. Spectral data
(1H and 13C NMR, IR, EA) for 36 was fully consistent
with that of (S)-(+)-fusarinolic acid, and the melting point
of the (+)-camphorsulfonate salt of synthetic 36 (188-
189 °C) was in good agreement with that previously
reported (187-188 °C) for the same derivative prepared
from authentic natural product.26
In summary, total syntheses of fusaric acid and (S)-
(+)-fusarinolic acid were completed in four and six steps
and in 35 and 33% overall yield, respectively. The
efficiency of these new synthetic routes compares very
favorably to those reported previously, highlighting the
utility of this approach to the synthesis of substituted
pyridines.
Our approach to the synthesis of fusaric acid and (S)-
(+)-fusarinolic acid begins with the synthesis of the
conjugated dienes 29 and 31 (Scheme 2). Metalation of
isoprene with LiTMP-potassium tert-butoxide29 and
alkylation with bromopropane furnished 2930 in 45% yield
as material (ca. 90% purity) suitable for use in the
subsequent Diels-Alder reaction without further puri-
fication. Alkylation of isoprene with (S)-(-)-propylene
oxide provided 30, which was protected as the corre-
sponding triisopropylsilyl ether (31) under standard
conditions.
Scheme 3 outlines the remainder of the synthesis of
fusaric acid. Reaction of oximinosulfonate 8 with 1.5
equiv of diene 29 according to our standard annulation
protocol provided methyl fusarate (20) in good overall
yield as a single regioisomer, and ester hydrolysis then
furnished synthetic fusaric acid in 85% yield following
purification by sublimation (0.1 mmHg, 110 °C). Spec-
1
troscopic and physical data (mp, H and 13C NMR, IR,
Rea r r a n gem en t of Oxim in osu lfon a te Cycloa d -
d u cts to P yr r olin es. As mentioned earlier, in the
course of our exploratory cycloaddition studies we ob-
served that the cycloadducts derived from certain disub-
stituted 1,3-dienes undergo a facile rearrangement upon
attempted purification. Exposure of the cycloaddition
product from the reaction of 8 with hexa-2,4-diene to
EA) for this material was fully consistent with that
previously reported for fusaric acid isolated from natural
sources.24b,g
Scheme 4 outlines the conversion of diene 31 to (S)-
(+)-fusarinolic acid. Reaction of oximinosulfonate 8 with
1.5 equiv of this diene using our standard annulation
procedure afforded the expected pyridine 33 in excellent
(31) The Mosher ester of racemic 34 was also prepared, and the
diastereomers were found to be well resolved by both 1H and 19F NMR
spectroscopy.
(32) The isolation of (S)-(+)-fusarinolic acid was complicated by its
high solubility in aqueous solution. Fortunately, (S)-(+)-fusarinolic acid
could be recovered from an appropriately buffered (pH 2.5) aqueous
solution by continuous liquid-liquid extraction with dichloromethane
for 2 days.
(29) Klusener, P. A. A.; Hommes, H. H.; Verkruijsse, H. D.;
Brandsma, L. Chem. Commun. 1985, 1677.
(30) For previous multistep routes to 29, see: (a) Korobova, L. M.;
Livshits, I. A. Zh. Obshch. Khim. 1964, 34, 3419. (b) Ueno, Y.; Sano,
H.; Aoki, S.; Okawara, M. Tetrahedron Lett. 1981, 28, 2675. (c)
Dzhemilev, U. M.; Ibragimov, A. G. J . Organomet. Chem. 1994, 466,
1.

Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates
J . Org. Chem., Vol. 63, No. 22, 1998 7845
Ta ble 2. Syn th esis of P yr r olin esa
Sch em e 5
a
Conditions: (a) 3.0 equiv of diene, 2.0 equiv of Me2AlCl, 1.0
silica gel, for example, resulted in formation of the
spirobicyclic pyrroline 38 (eq 7). This transformation,
which appears to involve migration of the vinylic carbon
in 37 to nitrogen with displacement of tosylate, is
reminiscent of the well-known Stieglitz rearrangement
equiv of 8, CH2Cl2, -78 °C; (b) CH3CN-pH 7 phosphate buffer
b
(10:1), 80 °C. Reaction time for rearrangement step b. c Isolated
overall yield for two steps.
the observed pyrroline products 42. Note that this
mechanism is consistent with our observation that cy-
cloadducts incorporating R1-substitution have the great-
est propensity to undergo rearrangement.35
As summarized in Table 2, we have found that under
the proper conditions a wide range of oximinosulfonate
Diels-Alder adducts can be converted to these interest-
ing pyrroline derivatives. Since it appeared likely that
the Stieglitz-type rearrangement is triggered by ioniza-
tion of the N-OTs bond, we focused our attention on
conditions that might promote ionization by stabilizing
charge separation. Initial experiments were carried out
on the cycloadduct derived from isoprene (12), which does
not rearrange under normal conditions. After some
experimentation, we found that heating this cycloadduct
in a mixture of acetonitrile and pH 7 phosphate buffer
(10:1) produces the desired pyrroline 48 in 55% yield.
Table 2 presents the results of the application of this
cycloaddition-rearrangement protocol to several dienes;
yields shown are overall isolated yields for the two-step
sequence. As expected, ketimines 48 and 49 are formed
in higher yield than the less stable aldimine 38. Note
that both penta-1,3-diene and hexa-2,4-diene produce the
same pyrroline product, as expected, since the carbon
bearing R1 is lost during rearrangement.
of N-chloroamines and hydroxylamine derivatives (e.g.,
N-OSO2Ar, N-OC(O)R). Stieglitz rearrangements in-
volving bridged bicyclic systems (e.g., eq 8) often proceed
under very mild conditions, and have been the subject of
extensive studies by Gassman33 and Hoffman,34 among
others.
Scheme 5 outlines a likely mechanism to account for
the rearrangement of the oximinosulfonate cycloadducts
41 to pyrrolines. Vinyl migration to nitrogen is most
likely concerted with ionization of tosylate, leading to an
iminium ion (44) or, alternatively, the product of ion pair
collapse (43). Addition of water then generates the
hemiaminal 45, which fragments as shown to produce
Rea ction of Oxim in osu lfon a te 8 w ith Cyclop en -
ta d ien e. The reaction of oximinosulfonate 8 with cyclo-
(33) (a) Gassman, P. G. Acc. Chem. Res. 1970, 3, 26 and references
therein. (b) Gassman, P. G.; Hartman, G. D. J . Am. Chem. Soc. 1973,
95, 449.
(34) Hoffman, R. V.; Kumar, A.; Buntain, G. A. J . Am. Chem. Soc.
1985, 107, 4731.
(35) We briefly conducted experiments with the aim of trapping the
putative intermediate 44 with cyanide ion. A variety of cyanide sources
and solvents were examined, but only the normal pyrroline product
could be isolated. Attack of cyanide at the sulfonyl group of 43 may be
responsible for pyrroline formation in these reactions.

7846 J . Org. Chem., Vol. 63, No. 22, 1998
Renslo and Danheiser
Sch em e 6
(the endo carbonyl) in 52. Although the yield of 51 is
modest, it is nonetheless striking that a product of such
structural complexity is formed in a single step from
cyclopentadiene.
Su m m a r y
The Me2AlCl-promoted cycloaddition of the new ox-
iminosulfonate 8 with conjugated dienes serves as the
key step in a regiocontrolled method for the synthesis of
substituted pyridines. Diels-Alder reactions of dieno-
phile 8 are highly regioselective and provide cycloadducts
with regiochemistry opposite to that obtained in hetero
Diels-Alder reactions involving imino dienophiles. The
utility of this new annulation strategy has been demon-
strated in efficient total syntheses of fusaric acid and (S)-
(+)-fusarinolic acid. Upon heating in a mixture of
acetonitrile and pH 7 phosphate buffer, the cycloadducts
also undergo an interesting Stieglitz-type rearrangement
producing novel substituted pyrrolines.
Exp er im en ta l Section
Ma ter ia ls. Commercial grade reagents and solvents were
used without further purification except as indicated below.
Methanol, toluene, benzene, dichloromethane, acetonitrile,
collidine, 2,2,6,6-tetramethylpiperidine, and triisopropylsilyl
trifluoromethanesulfonate were distilled from calcium hydride.
Tetrahydrofuran was distilled from sodium benzophenone
ketyl. N-Chlorosuccinimide was recrystallized from acetic
acid. Meldrum’s acid was recrystallized from acetone-water.
Tosyl chloride was recrystallized from diethyl ether at -78
°C. Isoprene was distilled at atmospheric pressure prior to
use. 2-tert-Butylbuta-1,3-diene and 1-vinylcyclohex-1-ene were
prepared as described by Korotkov and Roguleva37 except that
the dehydration was effected according to the general method
of Traynelis.38 2-(Triisopropylsilyloxy)buta-1,3-diene was pre-
pared as described previously.39 Cyclopentadiene was pre-
pared by thermal cracking of the dimer and stored at -60 °C
until needed. Sodium methoxide solution was freshly prepared
before use by the addition of sodium to methanol at 0 °C.
Gen er a l P r oced u r es. All reactions were performed in
flame-dried glassware under a positive pressure of argon and
stirred magnetically unless otherwise indicated. Air- and
moisture-sensitive liquids and solutions were transferred via
syringe or cannula and were introduced into reaction vessels
through rubber septa. Reaction product solutions were con-
centrated by using a Bu¨chi rotary evaporator at 15-20 mmHg.
Column chromatography was performed on EM Science silica
gel 60 (35-75 µm). Deactivated silica gel was prepared by
passing acetone through a column of silica gel followed by
drying in an oven at 120-130 °C for 2-4 h.
5-(Tosyloxyim in o)-2,2-d im e t h yl-1,3-d ioxa n e -4,6-d i-
on e (8). A 25-mL, round-bottomed flask equipped with an
argon inlet adapter and solid addition funnel was charged with
Meldrum’s acid (2.61 g, 18.1 mmol) and 13 mL of methanol.
To this suspension was added in one portion a solution of
sodium nitrite (1.25 g, 18.1 mmol) in 10 mL of water. The
reaction mixture was stirred for 2 h at room temperature to
give a deep red solution which was treated with 2.5 mL of pH
7 phosphate buffer and then cooled to 0 °C. Tosyl chloride
(3.11 g, 16.9 mmol) was added over 3 min via the solid addition
funnel, the cooling bath was removed, and the resulting peach-
colored mixture was stirred for 30 min and then filtered with
the aid of 30 mL of cold methanol. The resulting solid was
dried at 0.2 mmHg over P2O5 for 2 h to provide 3.02 g (57%
based on TsCl) of 8 as a white solid: mp 155-156 °C; IR
pentadiene led to the formation of a novel rearranged
product of a type not observed with any other dienes we
have examined to date. Thus, heating 8 with 5 equiv of
cyclopentadiene in toluene at 60 °C (sealed tube) for 2 h
produced two products, neither of which was the expected
cycloadduct (Scheme 6). The minor compound 50 was
identified as the product resulting from Stieglitz rear-
rangement of the Diels-Alder adduct 52, analogous to
the rearranged cycloadduct observed previously by Fleury
in the reaction of the bis-nitrile 4 with cyclopentadiene.36
The major product of the reaction (38% yield) was not so
1
easily identified, and inspection of its H and 13C NMR
spectra indicated that a major structural rearrangement
had occurred. An NMR DEPT experiment revealed the
presence of two methyl, two methylene, eight methine,
and six quaternary carbons, and these data, along with
2-D 1H NMR (TOCSY) data, eventually allowed the
assignment shown below for 51.
Scheme 6 presents a possible mechanistic pathway for
the transformation of the initially formed cycloadduct 52
to rearranged products 50 and 51. Ionization of the
N-OTs bond with anchimeric assistance by the alkene
generates a carbocation that is trapped by the endo
carbonyl group to produce the aziridine intermediate 53.
Elimination opens the dioxanedione ring, and attack of
tosylate on the resulting aziridinium ion 54 via pathway
c then generates the observed product 51. Interestingly,
no products derived from the alternative mode of cleavage
of the aziridinium ion (pathway d) were detected in this
reaction. This departure from normal Stieglitz-rear-
rangement chemistry is novel and most likely results
from the presence of an auspiciously situated nucleophile
(37) Korotkov, A. A.; Roguleva, L. F. Zh. Org. Khim. 1965, 1, 1180.
(38) Traynelis, V. J .; Hergenrother, W. L.; Livingston, J . R.; Vali-
centi, J . A. J . Org. Chem. 1962, 27, 2377.
(39) J ung, M. E.; McCombs, C. A.; Takeda, Y.; Pan, Y.-G. J . Am.
Chem. Soc. 1981, 103, 6677.
(36) (a) Fleury, J .-P.; Biehler, J .-M.; Desbois, M. Tetrahedron Lett.
1969, 4091. (b) Biehler, J .-M.; Fleury, J .-P. Tetrahedron 1971, 27, 3171.
(c) Fleury, J .-P.; Desbois, M. J . Heterocycl. Chem. 1978, 15, 1005.

Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates
(CHCl3) 3020, 1790, 1765, 1596, 1400, 1290 cm-1 1H NMR
(300 MHz, CDCl3) δ 1.78 (s, 6 H), 2.46 (s, 3 H), 7.40 (d, J )
8.4 Hz, 2 H), 7.93 (d, J ) 8.4 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 21.8, 28.1, 106.8, 129.5, 130.1, 130.2, 138.8, 147.1,
149.6, 154.7. Anal. Calcd for C13H13NO7S: C, 47.70; H, 4.00;
N, 4.28; Found: C, 47.76; H, 4.02; N, 4.22.
J . Org. Chem., Vol. 63, No. 22, 1998 7847
;
was allowed to warm to 0 °C, 20 mL of dichloromethane and
20 mL of water were added, and the aqueous phase was
separated and extracted with three 25-mL portions of dichlo-
romethane. The combined organic phases were washed with
30 mL of saturated NaCl solution, dried over MgSO4, filtered,
and concentrated to provide the cycloadduct as an orange foam.
A 100-mL, round-bottomed flask equipped with an argon
inlet adapter was charged with a solution of the cycloadduct
(prepared above) in 13 mL of THF and 13 mL of methanol.
The solution was cooled at 0 °C while NaOMe solution (1.51
M in methanol, 2.7 mL, 4.1 mmol) was added via syringe over
1 min followed by the addition of N-chlorosuccinimide (0.183
g, 1.37 mmol) in one portion. After the cooling bath was
removed, the solution was stirred in the dark for 16 h,
concentrated to ca. 5 mL, and then diluted with 30 mL of ethyl
acetate and 30 mL of pH 7 phosphate buffer. The aqueous
phase was separated and extracted with two 25-mL portions
of ethyl acetate, and the combined organic phases were
extracted with three 25-mL portions of 1.0 N HCl. The
combined acidic extracts were neutralized by the slow addition
of solid NaHCO3 and then extracted with three 30-mL portions
of ethyl acetate. The combined organic phases were washed
with 20 mL of saturated NaCl solution, dried over Na2SO4,
filtered, and concentrated onto 1 g of silica gel. The free-
flowing powder was placed at the top of a column of 10 g of
silica gel and eluted with 0-25% ethyl acetate-1% triethyl-
amine-hexane to provide 0.159 g (77%) of the pyridine 19 as a
colorless solid: mp 54-55 °C (petroleum ether); IR (CHCl3)
2950, 1695, 1420, 1295, 1107 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.43 (s, 3 H), 4.00 (s, 3H), 7.64 (dd, J ) 7.8, 2.0 Hz, 1 H),
8.05 (d, J ) 8.3 Hz, 1 H), 8.57 (d, J ) 2.0 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 18.5, 52.6, 124.6, 137.1, 137.3, 145.2, 150.2,
165.6. Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00, N, 9.27;
Found: C, 63.57, H, 6.24, N, 9.20.
9-(Tr iisop r op ylsiloxy)-3,3-d im eth yl-1,5-d ioxo-7-(tosyl-
oxy)-7-a za -2,4-d ioxa sp ir o[5.5]u n d ec-9-en e (11). A solution
of 2-(triisopropylsiloxy)buta-1,3-diene (0.366 g, 1.37 mmol) and
oximinosulfonate 8 (0.150 g, 0.458 mmol) in 8 mL of benzene
was heated at 55-60 °C for 24 h, cooled to room temperature,
and then concentrated to give a brown oil which was purified
by column chromatography on 10 g of deactivated silica
(elution with 0-25% ethyl acetate-hexane) to provide 0.142
g (56%) of 11 as a yellow oil: IR (CHCl3) 2950, 2370, 1755,
1
1390, 1310 cm-1; H NMR (300 MHz, CDCl3) δ 1.04 (d, J )
5.7 Hz, 18 H), 1.05-1.15 (m, 3 H), 1.72 (s, 3 H), 1.93 (s, 3 H),
2.47 (s, 3 H), 2.74 (m, 2 H), 3.87 (d, J ) 1.5 Hz, 2 H), 4.75 (m,
1 H), 7.36 (d, J ) 8.1 Hz, 2 H), 7.81 (d, J ) 8.4 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 12.4, 17.7, 21.7, 28.6, 29.2, 30.5, 56.2,
66.7, 95.3, 106.4, 129.3, 129.7, 131.2, 144.5, 146.0, 163.8.
Gen er a l P r oced u r e for Lew is Acid -P r om oted Rea c-
tion of Oxim in osu lfon a te 8 w ith Dien es. P r ep a r a tion
of
3,3,9-Tr im et h yl-1,5-d ioxo-7-(t osyloxy)-7-a za -2,4-d i-
oxa sp ir o[5.5]u n d ec-9-en e (12). A 50-mL, three-necked,
round-bottomed flask equipped with an argon inlet adapter,
glass stopper, and rubber septum was charged with a solution
of oximinosulfonate 8 (0.327 g, 1.00 mmol) and isoprene (0.204
g, 3.00 mmol) in 14 mL of dichloromethane. The solution was
cooled at -78 °C while Me2AlCl solution (1.0 M in hexane, 2.0
mL, 2.0 mmol) was added dropwise via syringe over 4 min.
The resulting orange solution was stirred for 4 h at -78 °C to
give a yellow solution which was quenched by addition of 3
mL of saturated sodium potassium tartrate solution. The
resulting mixture was allowed to warm to 0 °C, 15 mL of
dichloromethane and 15 mL of water were added, and the
aqueous phase was separated and extracted with three 20-
mL portions of dichloromethane. The combined organic phases
were washed with 30 mL of saturated NaCl solution, dried
over MgSO4, filtered, and concentrated to provide an orange
oil. Column chromatography on silica gel (elution with 1%
methanol-dichloromethane) provided 0.354 g (90%) of 12 as
Meth yl 5-n -Bu tylp yr id in e-2-ca r boxyla te (Meth yl Fu sa -
r a te) (20). Reaction of oximinosulfonate 8 (0.419 g, 1.28
mmol) with 3-methylenehept-1-ene (29) (0.200 g, 1.92 mmol)
and Me2AlCl (1.0 M in hexane, 2.6 mL, 2.6 mmol) in 11 mL of
dichloromethane at -78 °C for 4 h according to the general
procedure provided the crude cycloadduct as an orange foam.
Reaction of this material with NaOMe (1.42 M in methanol,
2.7 mL, 3.8 mmol) and NCS (0.171 g, 1.28 mmol) in 12 mL of
THF and 12 mL of methanol at room temperature for 15 h
according to the general procedure furnished 0.179 g (72%) of
pyridine 20 as a pale yellow oil: IR (film) 2990, 1725, 1440,
a white foam: IR (CHCl3) 3020, 1780, 1750, 1385, 1300 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.67 (s, 3 H), 1.69 (s, 3 H), 1.88
(s, 3 H), 2.48 (s, 3 H), 2.72 (br dd, J ) 1.2, 3.3 Hz, 2 H), 3.93
(s, 2 H), 5.33 (br dd, J ) 1.2, 3.6 Hz, 1 H), 7.36 (d, J ) 8.7 Hz,
2 H), 7.81 (d, J ) 8.4 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
20.3, 21.7, 28.5, 29.3, 32.8, 57.4, 66.3, 106.2, 113.9, 129.2,
129.55, 129.62, 131.2, 145.9, 164.0.
1
1310, 1120 cm-1; H NMR (300 MHz, CDCl3) δ 0.92 (tr, J )
7.5 Hz, 3 H), 1.31-1.35 (app hex, 2 H), 1.56-1.66 (app quint,
2 H), 2.65-2.70 (tr, J ) 7.5 Hz, 2 H), 3.98 (s, 3 H), 7.62 (dd, J
) 8.1, 1.9 Hz, 1 H), 8.04 (d, J ) 7.8 Hz, 1 H), 8.54 (d, J ) 1.8
Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 13.6, 22.1, 32.6, 32.8,
52.6, 124.8, 136.5, 142.1, 145.4, 149.9, 165.7. Anal. Calcd for
3,3,11-Tr im et h yl-1,5-d ioxo-7-(t osyloxy)-7-a za -2,4-d i-
oxa sp ir o[5.5]u n d ec-9-en e (13). Reaction of oximinosul-
fonate 8 (1.22 g, 3.73 mmol) with trans-penta-1,3-diene (0.761
g, 11.2 mmol) and Me2AlCl (1.0 M in hexane, 7.5 mL, 7.5 mmol)
in 37 mL of dichloromethane at -78 °C for 4 h according to
the general procedure furnished 1.15 g (78%) of cycloadduct
13 as a white solid: mp (dec) 133-145 °C; IR (CHCl3) 3005,
C
11H15NO2: C, 68.37; H, 7.82; N, 7.25; Found: C, 68.08; H,
7.91; N, 7.22.
Meth yl 5-ter t-Bu tylp yr id in e-2-ca r boxyla te (21). Reac-
tion of oximinosulfonate 8 (0.545 g, 1.66 mmol) with 2-tert-
butylbuta-1,3-diene (0.275 g, 2.49 mmol) and Me2AlCl (1.0 M
in hexane, 3.3 mL, 3.3 mmol) in 14 mL of dichloromethane at
-78 °C for 3.5 h according to the general procedure provided
the crude cycloadduct as a pink foam. Reaction of this
material with NaOMe (1.52 M in methanol, 3.3 mL, 5.0 mmol)
and NCS (0.222 g, 1.66 mmol) in 15 mL of THF and 15 mL of
methanol at room temperature for 14 h according to the
general procedure furnished 0.234 g (73%) of pyridine 21 as a
pale yellow oil: IR (film) 2960, 1740, 1720, 1435, 1315, 1125
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 9 H), 4.01 (s, 3 H),
7.82 (dd, J ) 8.1, 2.4 Hz, 1 H), 8.07 (d, J ) 8.1 Hz, 1 H), 8.79
(d, J ) 2.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 30.7, 33.9,
52.6, 124.5, 133.8, 145.1, 147.7, 149.9, 165.7.
1780, 1750, 1380, 1290 cm-1 1H NMR (300 MHz, CDCl3) δ
;
0.98 (d, J ) 7.5 Hz, 3 H), 1.70 (s, 3 H), 1.86 (s, 3 H), 2.47 (s, 3
H), 3.28-3.34 (m, 1 H), 4.03-4.09 (m, 2 H), 5.35-5.39 (dm, J
) 10.3 Hz, 1 H), 5.60-5.65 (dm, J ) 10.1 Hz, 1 H), 7.36 (d, J
) 8.0 Hz, 2 H), 7.81 (d, J ) 8.3 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 14.9, 21.8, 29.2, 29.5, 40.5(br), 54.3, 71.6, 106.5, 122.0,
125.5, 129.4, 129.6, 131.1, 146.0, 161.6, 164.9.
Gen er a l P r oced u r e for Tw o-Step P yr id in e An n u la -
tion . P r ep a r a tion of Meth yl 5-Meth ylp yr id in e-2-ca r -
boxyla te (19). A 50-mL, three-necked, round-bottomed flask
equipped with an argon inlet adapter, glass stopper, and
rubber septum was charged with a solution of oximinosul-
fonate 8 (0.450 g, 1.37 mmol) and isoprene (0.281 g, 4.13 mmol)
in 19 mL of dichloromethane. The solution was cooled at -78
°C while Me2AlCl solution (1.0 M in hexane, 2.7 mL, 2.7 mmol)
was added dropwise via syringe over 4 min. The resulting
orange solution was stirred for 3 h at -78 °C to give a yellow
solution which was quenched by addition of 4 mL of saturated
sodium potassium tartrate solution. The resulting mixture
Meth yl 3-Meth ylp yr id in e-2-ca r boxyla te (22). Reaction
of oximinosulfonate 8 (0.45 g, 1.37 mmol) with trans-penta-
1,3-diene (0.280 g, 4.12 mmol) and Me2AlCl (1.0 M in hexane,
2.7 mL, 2.7 mmol) in 20 mL of dichloromethane at -78 °C for
3 h according to the general procedure provided the crude
cycloadduct as a pink solid. Reaction of this material with
NaOMe (1.53 M in methanol, 2.7 mL, 4.1 mmol) and NCS

7848 J . Org. Chem., Vol. 63, No. 22, 1998
Renslo and Danheiser
(0.183 g, 1.37 mmol) in 13 mL of THF and 13 mL of methanol
at room temperature for 16 h according to the general
procedure furnished 0.117 g (57%) of pyridine 22 as a clear
Meth yl 5,6,7,8-Tetr a h yd r oqu in olin e-2-ca r boxyla te (28)
a n d Meth yl 5,6,7,8-tetr a h yd r oisoqu in olin e-1-ca r boxyla te
(27). Reaction of oximinosulfonate 8 (0.635 g, 1.94 mmol) with
1-vinylcyclohex-1-ene (0.315 g, 2.91 mmol) and Me2AlCl (1.0
M in hexane, 3.9 mL, 3.9 mmol) in 16 mL of dichloromethane
at -78 °C for 4 h according to the general procedure provided
the crude cycloadduct as an orange foam. Reaction of this
material with NaOMe (1.51 M in methanol, 3.9 mL, 5.8 mmol)
and NCS (0.259 g, 1.94 mmol) in 18 mL of THF and 18 mL of
methanol at room temperature for 16 h according to the
general procedure furnished 0.039 g (11%) of pyridine 28 as a
pale yellow oil and 0.184 g (50%) of pyridine 27 as a pale yellow
solid. For pyridine 28: IR (CHCl3) 2940, 1720, 1435, 1320,
1
colorless oil: IR (film) 2975, 1725, 1440, 1310, 1105 cm-1; H
NMR (300 MHz, CDCl3) δ 2.60 (s, 3H), 3.99 (s, 3 H), 7.31 (dd,
J ) 7.8, 3.9 Hz, 1 H), 7.58 (dd, J ) 7.8, 2.9 Hz, 1 H), 8.51 (dd,
J ) 4.4, 1.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 19.8, 52.3,
125.8, 135.4, 139.7, 146.7, 146.8, 166.3.
Meth yl 3-(4-Meth ylp en t-3-en yl)p yr id in e-2-ca r boxyla te
(23). Reaction of oximinosulfonate 8 (0.384 g, 1.17 mmol) with
8-methylnona-1,3(E),7-triene (0.240 g, 1.76 mmol) and Me2-
AlCl (1.0 M in hexane, 2.3 mL, 2.3 mmol) in 16 mL of
dichloromethane at -78 °C for 3 h according to the general
procedure provided the crude cycloadduct as an orange oil.
Reaction of this material with NaOMe (1.40 M in methanol,
2.5 mL, 3.5 mmol) and NCS (0.156 g, 1.17 mmol) in 11 mL of
THF and 11 mL of methanol at room temperature for 20 h
according to the general procedure furnished 0.139 g (54%) of
pyridine 23 as a clear colorless oil: IR (film) 2960, 2930, 1730,
1450, 1430, 1305, 1200, 1135, 1110, 1090 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.41 (s, 3 H), 1.61 (s, 3 H), 2.25 (app q, J ) 8
Hz, 2 H), 2.91 (t, J ) 8 Hz, 2 H), 3.93 (s, 3 H), 5.09 (t, J ) 7
Hz, 1 H), 7.30 (dd, J ) 5, 8 Hz, 1 H), 7.55 (d, J ) 7 Hz, 1 H),
8.49 (d, J ) 5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 17.4,
25.5, 29.4, 32.7, 52.5, 122.7, 125.7, 132.9, 139.0, 139.1, 146.7,
147.2, 166.4.
1
1130 cm-1; H NMR (300 MHz, CDCl3) δ 1.82-1.94 (m, 4 H),
2.84 (tr, J ) 6.4 Hz, 2 H), 3.03 (tr, J ) 6.7 Hz, 2 H), 3.98 (s, 3
H), 7.49 (d, J ) 7.8 Hz, 1 H), 7.88 (d, J ) 7.8 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 22.3, 22.8, 29.0, 32.7, 52.7, 122.5,
136.7, 137.4, 145.1, 158.0, 166.1. For pyridine 27: mp 68-69
°C (petroleum ether) IR (CHCl3) 3020, 2970, 1720, 1435, 1210
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.79-1.82 (m, 4 H), 2.80-
2.84 (m, 2 H), 3.02-3.06 (m, 2 H), 3.96 (s, 3 H), 7.13 (d, J )
4.8 Hz, 1 H), 8.36 (d, J ) 4.8 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 21.6, 22.4, 25.9, 29.5, 52.4, 126.6, 134.5, 145.6, 147.5,
148.2, 166.8. Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85;
N, 7.32; Found: C, 69.10; H, 6.98; N, 7.23.
3-Meth ylen eh ep t-1-en e (29). A solution of KOt-Bu (1.65
g, 14.7 mmol) and 2,2,6,6-tetramethylpiperidine (2.08 g, 14.7
mmol) in 12 mL of THF was cooled at -65 °C while n-BuLi
solution (2.5 M in hexane, 5.9 mL, 14.7 mmol) was added
dropwise via syringe over 2 min. The resulting orange solution
was cooled at -78 °C while isoprene (1.50 g, 22.1 mmol) was
added dropwise via syringe over 10 min. The resulting red
solution was stirred for 10 min at -78 °C, and then a solution
of 1-bromopropane (2.72 g, 22.1 mmol) in 3 mL of THF was
added dropwise via cannula over 30 s. The resulting yellow
suspension was stirred for 20 min at -50 °C, the cooling bath
was removed, and the solution was allowed to warm to 0 °C.
The yellow suspension was then quenched by addition of 40
mL of water, and the resulting solution was extracted with
three 25-mL portions of ether. The combined organic phases
were washed with two 20-mL portions of 1 N HCl solution and
30 mL of saturated NaCl solution, dried over MgSO4, filtered,
and then concentrated by distillation at atmospheric pressure.
The pale yellow residue was purified by column chromatog-
raphy (elution with pentane), and the resulting pentane
solution was concentrated by distillation at atmospheric pres-
sure to give 0.687 g (45%, ca. 90% pure) of the diene 29 as a
colorless oil, used in the next step without further purification.
5-n -Bu tylp yr id in e-2-ca r boxylic Acid (F u sa r ic Acid )
(32). To a solution of methyl fusarate (20) (0.126 g, 0.652
mmol) in 2 mL of methanol and 0.5 mL of water at 0 °C was
added LiOH-H2O (0.239 g, 3.26 mmol) in one portion. The
resulting mixture was stirred for 1 h at 0 °C, and then the
cooling bath was removed and the solution was diluted with 2
mL of water, acidified to pH 2 by slow addition of 1.0 N HCl,
and then extracted with eight 10-mL portions of EtOAc. The
combined organic phases were dried over MgSO4, filtered, and
concentrated to provide a white solid. Sublimation at 0.1
mmHg and ca. 100 °C provided 0.099 g (85%) of fusaric acid
(32) as a white solid: mp 99-100.5 °C; IR (CHCl3) 2960, 2930,
Meth yl 3,5-Dim eth ylp yr id in e-2-ca r boxyla te (24). Re-
action of oximinosulfonate 8 (0.450 g, 1.37 mmol) with a 70:
30 mixture of trans-2-methylpenta-1,3-diene and 4-methylpenta-
1,3-diene (0.452 g, 5.5 mmol) and Me2AlCl (1.0 M in hexane,
2.7 mL, 2.7 mmol) in 20 mL of dichloromethane at -78 °C for
1 h according to the general procedure provided the crude
cycloadduct as a yellow foam. Reaction of this material with
NaOMe (1.53 M in methanol, 2.7 mL, 4.4 mmol) and NCS
(0.183 g, 1.37 mmol) in 15 mL of THF and 15 mL of methanol
at room temperature for 16 h according to the general
procedure furnished 0.159 g (70%) of pyridine 24 as a colorless
solid: mp 42-43 °C (petroleum ether); IR (CHCl3) 2960, 1710,
1
1440, 1305, 1095 cm-1; H NMR (300 MHz, CDCl3) δ 2.34 (s,
3 H), 2.56 (s, 3 H), 3.94 (s, 3 H), 7.39 (s, 1 H), 8.35 (s, 1 H); 13
C
NMR (75 MHz, CDCl3) δ 18.2, 20.0, 52.4, 135.6, 136.4, 140.4,
144.1, 147.4, 166.5. Anal. Calcd for C9H11NO2: C, 65.44; H,
6.71; N, 8.48; Found: C, 64.59; H, 6.80; N, 8.40.
Meth yl 3,4-Dim eth ylp yr id in e-2-ca r boxyla te (25). Re-
action of oximinosulfonate 8 (0.452 g, 1.38 mmol) with 3-meth-
ylpenta-1,3-diene (0.340 g, 4.14 mmol) and Me2AlCl (1.0 M in
hexane, 2.8 mL, 2.8 mmol) in 19 mL of dichloromethane at
-78 °C for 2.5 h according to the general procedure provided
the crude cycloadduct as an orange foam. Reaction of this
material with NaOMe (1.52 M in methanol, 2.7 mL, 4.1 mmol)
and NCS (0.184 g, 1.38 mmol) in 12 mL of THF and 12 mL of
methanol at room temperature for 14 h according to the
general procedure furnished 0.091 g (40%) of pyridine 25 as a
pale yellow oil: IR (CHCl3) 2900, 1725, 1440, 1300, 1190, 1055
cm-1; 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3 H), 2.43 (s, 3 H),
3.96 (s, 3 H), 7.19 (d, J ) 4.9 Hz, 1 H), 8.36 (d, J ) 4.9 Hz, 1
H); 13C NMR (75 MHz, CDCl3) δ 14.9, 19.9, 52.5, 127.0, 133.1,
146.3, 147.8, 148.8, 167.3.
Meth yl 3,6-Dim eth ylp yr id in e-2-ca r boxyla te (26). Re-
action of oximinosulfonate 8 (0.600 g, 1.83 mmol) with tran-
s,trans-hexa-2,4-diene (0.451 g, 5.49 mmol) and Me2AlCl (1.0
M in hexane, 3.7 mL, 3.7 mmol) in 25 mL of dichloromethane
at -78 °C for 1.5 h according to the general procedure provided
the crude cycloadduct as a pink foam. Reaction of this
material in 20 mL of THF and 20 mL of methanol at room
temperature with NaOMe in three portions (1.51 M in metha-
nol, 6.0 mL total, 9.2 mmol, 5.0 equiv) and NCS in two portions
(0.489 g, 7.3 mmol, 4.0 equiv) for 13 h according to the general
procedure furnished 0.120 g (40%) of pyridine 26 as a colorless
oil: IR (film) 2950, 1725, 1435, 1320, 1100 cm-1; 1H NMR (300
MHz, CDCl3) δ 2.53 (s, 3 H), 2.59 (s, 3 H), 3.97 (s, 3H), 7.20
(d, J ) 8.0 Hz, 1 H), 7.49 (d, J ) 7.8 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 19.3, 23.9, 52.4, 125.6, 131.8, 140.0, 146.5,
155.6, 166.7.
1765, 1410, 1355, 1295 cm-1 1H NMR (300 MHz, CDCl3) δ
;
0.95 (t, J ) 7.3 Hz, 3 H), 1.35-1.45 (app hex, J ) 7.3 Hz 2 H),
1.60-1.70 (m, 2 H), 2.73 (t, J ) 7.6 Hz, 2 H), 7.75 (dd, J )
8.0, 2.1 Hz, 1 H), 8.14 (d, J ) 8.0, 1 H), 8.44 (d, J ) 1.5 Hz, 1
H), 11.8 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 13.7, 22.2,
32.7, 32.8, 124.5, 138.5, 143.0, 145.0, 147.6, 165.3. Anal. Calcd
for C10H13NO2: C, 67.02; H, 7.31; N, 7.82; Found: C, 67.10;
H, 7.27; N, 7.66.
(S)-5-Meth ylen eh ep t-6-en -2-ol (30). A solution of KOt-
Bu (0.310 g, 2.75 mmol) and 2,2,6,6-tetramethylpiperidine
(0.388 g, 2.75 mmol) in 3 mL of THF was cooled at -60 °C
while n-BuLi solution (2.55 M in hexane, 1.1 mL, 2.8 mmol)
was added dropwise via syringe over 2 min. The resulting
orange solution was cooled at -78 °C while isoprene (0.28 g,
4.1 mmol) was added dropwise via syringe over 5 min. The

Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates
J . Org. Chem., Vol. 63, No. 22, 1998 7849
resulting red solution was stirred for 10 min at -60 to -70
°C, and then a solution of (S)-propylene oxide (0.240 g, 4.13
mmol) in 1 mL of THF was added dropwise via cannula over
2 min. The resulting deep red solution was stirred for 10 min
at -50 °C and allowed to warm to room temperature, and the
mixture was then quenched by addition of 10 mL of water and
extracted with six 10-mL portions of ether. The combined
organic phases were washed with two 10-mL portions of 0.5
N HCl solution, and the combined acidic phases were back-
extracted with two 10-mL portions of ether. The combined
organic phases were dried over MgSO4, filtered, and concen-
trated onto 1.4 g of silica gel. This free-flowing powder was
transferred to the top of a column of 16 g of silica gel and eluted
with 0-25% ethyl acetate-0.1% methanol-hexane to provide
fusarinolate (34) as a colorless oil: [R]25 +17.9° (CHCl3, c )
D
1.13); IR (film) 3370, 2960, 1725, 1570, 1310 cm-1; H NMR
1
(300 MHz, CDCl3) δ 1.25 (d, J ) 6.2 Hz, 3 H), 1.52 (br s, 1 H),
1.74-1.82 (m, 2 H), 2.72-2.93 (m, 2 H), 3.80-3.86 (app hex,
J ) 6.2 Hz, 1 H), 3.99 (s, 3 H), 7.67 (dd, J ) 8.0, 2.3 Hz, 1 H),
8.06 (d, J ) 8.0 Hz, 1 H), 8.59 (d, J ) 2.0 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 23.7, 29.2, 39.9, 52.6, 66.9, 124.9, 136.6,
141.6, 145.7, 150.0, 165.7.
(S)-5-(3-Hyd r oxybu tyl)p yr id in e Ca r boxylic Acid ((S)-
F u sa r in olic Acid ) (36). A flask charged with (S)-methyl
fusarinolate 34 (0.128 g, 0.610 mmol) was cooled at 0 °C while
KOH solution (1.0 M in methanol, 4.6 mL, 4.6 mmol) and then
1.2 mL of water was added. The resulting solution was stirred
for 2 h at 0 °C, concentrated to ca. 1 mL, and treated with 10
mL of pH 2.5 phosphate buffer. The resulting solution was
subjected to continuous liquid-liquid extraction with 20 mL
of dichloromethane for 2 days. The dichloromethane phase
was dried over Na2SO4, filtered, and concentrated to give 0.120
g of a colorless oil. Attempted recrystallization from dichlo-
romethane-methanol gave an oil which solidified upon drying
at 0.1 mmHg to provide 0.097 g (82%) of (S)-fusarinolic acid
0.212 g (61%) of the diene 30 as a pale yellow oil: [R]25 +16°
D
(CHCl3, c ) 2.70); IR (film) 3340, 2960, 2925, 1595, 1080 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.23 (d, J ) 6.3 Hz, 3 H), 1.43
(br s, 1H), 1.62-1.69 (app quart, J ) 7.8 Hz, 2 H), 2.24-2.40
(m, 2 H), 3.82-3.88 (app hex, J ) 6.0 Hz, 1 H), 5.03 (s, 2 H),
5.08 (d, J ) 10.8 Hz, 1 H), 5.26 (d, J ) 17.4 Hz, 1 H), 6.38 (dd,
J ) 17.7, 11.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 23.5,
27.5, 37.6, 67.8, 113.3, 115.7, 138.7, 146.1.
(36) as colorless crystals: mp 108-109 °C; [R]25 +20.5°
D
1
(S)-2-(Tr iisop r op ylsiloxy)-5-m eth ylen eh ep t-6-en e (31).
A solution of diene 30 (0.349 g, 2.76 mmol) in 4 mL of
dichloromethane was cooled at 0 °C while collidine (0.836 g,
6.90 mmol) was added dropwise via syringe over 2 min followed
by the addition of triisopropylsilyl trifluoromethanesulfonate
(1.1 g, 0.97 mL, 3.6 mmol) over 10 min. The resulting solution
was stirred for 1.5 h at 0 °C, diluted with 20 mL of dichlo-
romethane, and then washed with 20 mL of 1.0 N HCl. The
acid extracts were back-extracted with 10 mL of dichlo-
romethane, and the combined organic phases were washed
with 15 mL of saturated NaCl solution, dried over MgSO4,
filtered, and concentrated to give a colorless oil. Purification
by column chromatography on silica gel (elution with 1%
triethylamine-hexane) provided 0.720 g (92%) of the diene 31
as a colorless oil: [R]25D +2.6° (CHCl3, c ) 2.8); IR (film) 2940,
(MeOH, c ) 1.05); IR (KBr) 3265, 2870, 2420, 1660 cm-1; H
NMR (300 MHz, DMSO-d6) δ 1.08 (d, J ) 6.0 Hz, 3 H), 1.60-
1.67 (app quart, J ) 6.2 Hz, 2 H), 2.62-2.82 (m, 2 H), 3.53-
3.61 (app hex, J ) 6.0 Hz, 1 H), 4.2-4.8 (br s, 1 H), 7.79 (dd,
J ) 8.1, 1.9 Hz, 1 H), 7.95 (d, J ) 8.1 Hz, 1 H), 8.54 (d, J )
1.7, 1 H), 11.8-13.2 (br s, 1 H); 13C NMR (75 MHz, CD3OD) δ
23.7, 30.3, 41.2, 67.7, 126.4, 140.1, 144.4, 146.9, 149.6, 167.2.
Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18.
Found: C, 61.24; H, 6.71; N, 7.03.
Gen er a l P r oced u r e for Tw o-Step P yr r olin e An n u la -
tion . P r ep a r a tion of 2,8,8-Tr im eth yl-6,10-d ioxo-1-a za -
7,9-d ioxa sp ir o[4.5]d ec-1-en e (48). A 50-mL, three-necked,
round-bottomed flask equipped with an argon inlet adapter,
glass stopper, and rubber septum was charged with a solution
of oximinosulfonate 8 (0.328 g, 1.00 mmol) and isoprene (0.204
g, 3.00 mmol) in 12 mL of dichloromethane. The solution was
cooled at -78 °C while Me2AlCl solution (1.0 M in hexane, 2.0
mL, 2.0 mmol) was added dropwise via syringe over 4 min.
The resulting orange solution was stirred for 3 h at -78 °C to
give a yellow solution which was quenched by addition of 3
mL of saturated sodium potassium tartrate solution. The
resulting mixture was allowed to warm to 0 °C, 20 mL of
dichloromethane and 20 mL of water were added, and the
aqueous phase was separated and extracted with three 20-
mL portions of dichloromethane. The combined organic phases
were washed with 30 mL of saturated NaCl solution, dried
over MgSO4, filtered, and concentrated to provide the crude
cycloadduct as a yellow foam.
A 100-mL, round-bottomed flask equipped with an argon
inlet adapter and reflux condenser was charged with a solution
of the crude cycloadduct in 21 mL of acetonitrile and 2.5 mL
of pH 7 phosphate buffer. The resulting solution was heated
at 80 °C for 30 min, allowed to cool to room temperature, and
concentrated to ca. 2 mL. The residue was diluted with 15 mL
of dichloromethane and 15 mL of water, and the aqueous phase
was separated and extracted with three 20-mL portions of
dichloromethane. The combined organic extracts were dried
over MgSO4, filtered, and concentrated onto 1 g of deactivated
silica gel. This free-flowing powder was transferred to the top
of a column of 10 g of deactivated silica gel and eluted with
0-25% ethyl acetate-hexane to provide 0.089 g (42%) of the
pyrroline 48 as a colorless oil: IR (CHCl3) 3015, 1745, 1635,
1300 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.78 (s, 3 H), 2.05 (s,
3 H), 2.12 (s, 3 H), 2.58 (tr, J ) 7.5 Hz, 2 H), 2.94 (tr, J ) 7.5
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 19.5, 28.5, 28.8, 31.7,
41.5, 81.0, 106.4, 167.7, 183.2.
1
1595, 1460, 1095 cm-1; H NMR (300 MHz, CDCl3) δ 1.07 (s,
21 H), 1.20 (d, J ) 6.0 Hz, 3 H), 1.58-1.72 (m, 2 H), 2.23-
2.31 (m, 2 H), 3.96-4.02 (app hex, J ) 5.9 Hz, 1H), 5.00 (s, 2
H), 5.06 (d, J ) 10.8 Hz, 1 H), 5.24 (d, J ) 17.7 Hz, 1 H), 6.37
(dd, J ) 17.7, 10.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 12.5,
18.1, 18.2, 23.5, 27.1, 38.5, 68.4, 113.2, 115.4, 138.9, 146.6.
(S)-Meth yl 5-(3-(Tr iisop r op ylsiloxy)bu tyl)p yr id in e-2-
ca r boxyla te (33). Reaction of oximinosulfonate 8 (0.494 g,
1.51 mmol) with diene 31 (0.640 g, 2.27 mmol) and Me2AlCl
(1.0 M in hexane, 3.0 mL, 3.0 mmol) in 13 mL of dichlo-
romethane at -78 °C for 3 h according to the general procedure
provided the crude cycloadduct as an orange oil. Reaction of
this material with NaOMe (1.44 M in methanol, 3.1 mL, 4.5
mmol) and NCS (0.202 g, 1.51 mmol) in 15 mL of THF and 15
mL of methanol at room temperature for 16 h according to
the general procedure furnished 0.428 g (78%) of pyridine 33
as a pale yellow oil: [R]25 +0.86° (CHCl3, c ) 1.97); IR (film)
D
2940, 1745, 1720, 1310 cm-1
;
1H NMR (300 MHz, CDCl3) δ
1.07 (s, 21 H), 1.24 (d, J ) 6.0 Hz, 3 H), 1.76-1.83 (m, 2 H),
2.76-2.81 (m, 2 H), 4.00 (s, 3 H), 4.04 (app hex, J ) 5.9 Hz, 1
H), 7.65 (dd, J ) 8.0, 1.7 Hz, 1 H), 8.06 (d, J ) 8.0 Hz, 1 H),
8.57 (d, J ) 2.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 12.4,
18.11, 18.07, 23.3, 28.5, 40.9, 52.7, 67.6, 124.9, 136.5, 142.3,
145.5, 150.0, 165.8.
(S)-Meth yl 5-(3-Hyd r oxybu tyl)p yr id in e-2-ca r boxyla te
((S)-Meth yl F u sa r in ola te) (34). A solution of pyridine 33
(0.079 g, 0.22 mmol) in 2.2 mL of THF was treated with
tetrabutylammonium fluoride solution (1.0 M in THF, 0.24 mL,
0.24 mmol) dropwise via syringe over 1 min. The resulting
orange solution was stirred for 2 h at room temperature and
then quenched by addition of 2 mL of saturated NH4Cl
solution. The resulting mixture was stirred for 15 min, diluted
with 10 mL of water, and extracted with eight 5-mL portions
of EtOAc. The combined organic phases were dried over
MgSO4, filtered, and concentrated onto 0.4 g of silica gel. This
free-flowing powder was transferred to the top of a column of
5 g of silica gel and eluted with 1% triethylamine-0.1%
methanol-ethyl acetate to furnish 0.042 g (93%) of (S)-methyl
2,4,8,8-Tet r a m et h yl-6,10-d ioxo-1-a za -7,9-d ioxa sp ir o-
[4.5]d ec-1-en e (49). Reaction of oximinosulfonate 8 (0.328
g, 1.00 mmol) with a 70:30 mixture of trans-2-methylpenta-
1,3-diene and 4-methylpenta-1,3-diene (0.329 g, 4.00 mmol)
and Me2AlCl (1.0 M in hexane, 2.0 mL, 2.0 mmol) in 12 mL of
dichloromethane at -78 °C for 1 h according to the general
procedure provided the crude cycloadduct as an orange foam.

7850 J . Org. Chem., Vol. 63, No. 22, 1998
Renslo and Danheiser
Heating this material in 21 mL of acetonitrile and 2.5 mL of
pH 7 phosphate buffer at 80 °C for 45 min according to the
general procedure furnished 0.102 g (45%) of pyrroline 49 as
a white solid: mp 108-109 °C; IR (CHCl3) 2990, 1780, 1750,
(38%) of 7-oxo-1-(propenoxycarbonyl)-4-(tosyloxy)-3,8-methano-
2-aza-6-oxabicyclo[3.2.1]octane (51) as a white solid and 0.021
g (9%) of 3,3-dimethyl-1,5-dioxo-8-tosyloxy-7,10-etheno-7-aza-
2,4-dioxaspiro[5.4]decane (50). For 7-oxo-1-(propenoxycarbo-
nyl)-4-(tosyloxy)-3,8-methano-2-aza-6-oxabicyclo[3.2.1]octane
(51): mp 135-137 °C; IR (CHCl3) 3345, 3030, 1800, 1755,
1
1630 cm-1; H NMR (300 MHz, CDCl3) δ 1.14 (d, J ) 6.9 Hz,
3 H), 1.76 (s, 3H), 1.90 (s, 3 H), 2.14 (s, 3 H), 2.76 (dd, J )
16.8, 9.6 Hz, 1 H), 2.85 (dd, J ) 16.8, 8.4 Hz, 1 H), 3.16 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 20.1, 27.8, 29.9, 44.1,
1
1375, 1175, 995 cm-1; H NMR (300 MHz, CDCl3) δ 1.75 (dq,
J ) 12.1, 1.8 Hz, 1H), 1.94 (s, 3 H), 2.17 (d, J ) 12.9 Hz, 1 H),
2.48 (s, 3 H), 2.5-2.7 (br s, 1 H), 3.61 (dq, J ) 5.1, 1.4 Hz, 1
H), 3.76 (s, 1 H), 4.31 (app t, J ) 1.7 Hz, 1 H), 4.68 (dd, J )
5.1, 1.4 Hz, 1 H), 4.77 (s, 2 H), 7.39 (d, J ) 7.8 Hz, 2 H), 7.81
(d, J ) 8.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 19.1, 21.8,
33.2, 50.1, 59.9, 66.4, 81.9, 82.6, 102.8, 127.8, 130.2, 132.4,
145.6, 152.4, 166.0, 172.2. For 3,3-dimethyl-1,5-dioxo-8-(to-
syloxy)-7,10-etheno-7-aza-2,4-dioxaspiro[5.4]decane (50): IR
47.4, 83.1, 105.8, 165.9, 168.8, 184.9. Anal. Calcd for C11H15
-
NO4: C, 58.66; H, 6.71; N, 6.22; Found: C, 58.79; H, 6.68; N,
6.02.
4,8,8-Tr im eth yl-6,10-dioxo-1-aza-7,9-dioxaspir o[4.5]dec-
1-en e (38). Reaction of oximinosulfonate 8 (0.328 g, 1.00
mmol) with trans-hexa-2,4-diene (0.246 g, 3.00 mmol) and Me2-
AlCl (1.0 M in hexane, 2.0 mL, 2.0 mmol) in 12 mL of
dichloromethane at -78 °C for 3 h according to the general
procedure provided the crude cycloadduct as a yellow foam.
Heating this material in 20 mL of acetonitrile and 2.5 mL of
pH 7 phosphate buffer at 80 °C for 10 min according to the
general procedure furnished 0.073 g (35%) of pyrroline 38 as
a white solid: mp 102-106 °C; IR (CHCl3) 2990, 1780, 1745,
(CHCl3) 3020, 1780, 1740, 1380, 1320, 1180, 1055 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 1.71 (s, 3 H), 1.94 (dd, J ) 12.9, 6.7
Hz, 1 H), 2.21 (s, 3 H), 2.45 (s, 3 H), 2.66 (dtr, J ) 12.9, 2.6
Hz, 1 H), 3.43 (tr, J ) 3.0 Hz, 1 H), 5.23 (dd, J ) 6.7, 2.4 Hz,
1 H), 6.04 (d, J ) 3.8 Hz, 1 H), 6.65 (dd, J ) 3.8, 3.0 Hz, 1 H),
7.34 (d, J ) 7.9 Hz, 2 H), 7.76 (d, J ) 8.3 Hz, 2 H); 13C NMR
(125 MHz, CDCl3) δ 21.6, 26.7, 30.0, 30.5, 44.5, 82.3, 93.9,
108.3, 127.5, 129.8, 133.9, 134.5, 140.1, 145.1, 162.34, 162.32.
1
1620 cm-1; H NMR (300 MHz, CDCl3) δ 1.18 (d, J ) 7.2 Hz,
3 H), 1.79 (s, 3 H), 1.93 (s, 3H), 2.69 (dd, J ) 17.4, 9.0 Hz, 1
H), 2.98 (dd, J ) 18.6, 8.7 Hz, 1 H), 3.12 (m, 1 H), 7.99 (s, 1
H); 13C NMR (75 MHz, CDCl3) δ 14.1, 27.8, 29.8, 42.5, 45.6,
83.1, 106.0, 165.1, 168.2, 175.5.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 28273) for generous financial
support.
7-Oxo-1-(pr open oxycar bon yl)-4-(tosyloxy)-3,8-m eth an o-
2-a za -6-oxa bicyclo[3.2.1]octa n e (51) a n d 3,3-Dim eth yl-
1,5-d ioxo-8-(tosyloxy)-7,10-eth en o-7-a za -2,4-d ioxa sp ir o-
[5.4]d eca n e (50). A threaded Pyrex tube (ca. 50 mL capacity)
equipped with a rubber septum and argon inlet needle was
charged with oximinosulfonate 8 (0.198 g, 0.605 mmol),
cyclopentadiene (0.200 g, 3.02 mmol), and 20 mL of toluene.
The tube was then sealed with a Teflon cap and heated at 60
°C for 2 h. After cooling to room temperature, the resulting
orange solution was concentrated, and the residual orange oil
was purified by column chromatography on 12 g of silica gel
(elution with 25% ethyl acetate-hexane) to provide 0.090 g
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
all pyridine and pyrroline annulation products, as well as
compounds 30, 31, 32, 34, 36, 50, and 51 (24 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 O981014E