Photocycloaddition of four-carbon-tethered pyridones. Intramolecular hydrogen bonding and facilitated amide hydrolysis by a proximal secondary alcohol

Article abstract of DOI:10.1021/jo025565n

Four-carbon-tethered pyridones undergo photocycloaddition to give exclusively trans-[4 + 4] products. The presence of a tether alcohol engenders a solvent-dependent diastereoselectivity for the cycloaddition by intramolecular hydrogen bonding to the adjacent pyridone. Following cycloaddition, the alcohol can deliver a carbonyl group to the proximal, hindered amide nitrogen, leading to a very facile amide hydrolysis.

Full text of DOI:10.1021/jo025565n

J . Org. Chem. 2002, 67, 3487-3493
3487
P h otocycloa d d ition of F ou r -Ca r bon -Teth er ed P yr id on es.
In tr a m olecu la r Hyd r ogen Bon d in g a n d F a cilita ted Am id e
Hyd r olysis by a P r oxim a l Secon d a r y Alcoh ol1
Man Zhu, Zhilei Qiu, Gary P. Hiel,2 and Scott McN. Sieburth*
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
sieburth@astro.temple.edu
Received J anuary 29, 2002
Four-carbon-tethered pyridones undergo photocycloaddition to give exclusively trans-[4 + 4]
products. The presence of a tether alcohol engenders a solvent-dependent diastereoselectivity for
the cycloaddition by intramolecular hydrogen bonding to the adjacent pyridone. Following
cycloaddition, the alcohol can deliver a carbonyl group to the proximal, hindered amide nitrogen,
leading to a very facile amide hydrolysis.
Functional groups often play an important role as
stereocontrol elements and as points of leverage for
otherwise difficult reactivity. The intimate proximity of
functional groups in 2-pyridone photodimers makes this
interplay an important aspect of their chemistry. Our
studies of intramolecular 2-pyridone photocycloadditions
revealed that chirality on the tether can exert stereocon-
trol; hydrogen bonding by an alcohol to an adjacent
pyridone carbonyl can bias the product distribution in
favor of one diastereomer, whereas protection of the
alcohol as a tert-butyldimethylsilyl ether leads to another
diastereomer exclusively.3-5 Most of these findings were
in the context of three-carbon tethered pyridones. We
describe here new followup studies of the synthesis and
photocycloaddition of the four-carbon-tethered bis-2-
pyridone 2 and a remarkably facile hydrolysis of the
secondary amide of 1 mediated stereospecifically by the
adjacent hydroxyl.
P h otosu bstr a te P r ep a r a tion . We reported the cy-
cloaddition of 2 to give 1 in 1991, Figure 1.6 Product 1
F igu r e 1. Intramolecular photoproduct 1 and its precursor
2, which can be prepared from 3 or 6.
was identified as a mixture of two isomers differing only
in the alcohol stereochemistry, but their identity was not
verified.6 To clear up this point as well as to investigate
the subsequent chemistry of 1, we required additional
material; however, the original synthesis of 2 from 3
involved several difficult steps and intermediates such
as 4 that were not readily available. We therefore began
our reinvestigation exploring alternative synthetic routes
to 2 via 6, which in turn could be obtained from either 7
or 8.
tion.7,8 Hydrogenation of 7 under acidic conditions pre-
serves the pyridine ring to yield 5,6,7,8-tetrahydroquin-
oline in moderate yield, Scheme 1.9-11 Treatment of this
product with iodomethane cleanly and quantitatively
gave methiodide 97 and set the stage for Decker oxida-
tion. Weber had shown that treatment of 9 with basic
potassium ferricyanide led to oxidative cleavage of the
saturated ring with concomitant formation of a pyridone
carboxylic acid. This sequence generates one of the
pyridone rings and all the carbons of the tether in only
three steps. Fischer esterification and reduction of the
ester with DIBAL gave conversion to alcohol 10 in high
yield. While this sequence provided gram quantities of
10, the overall yield was below 20%, prompting consid-
eration of alternative approaches.
Quinoline 7 contains all of the carbons of 6 except the
N-methyl group, and conversion of 7 to 6 could take
advantage of Weber’s investigations of the Decker oxida-
* To whom correspondence should be addressed. Fax: 215-204-1532.
(1) Taken, in part, from: Zhu, M. M. S. Ph.D. Dissertation, SUNY
Stony Brook, 1999; Qiu, Z. M. S. Ph.D. Dissertation, SUNY Stony
Brook, 1998; Hiel, G. P. Ph.D. Dissertation, SUNY Stony Brook, 1997.
(2) Current address: Dowling College, Oakdale, NY 11769.
(3) Sieburth, S. McN.; J oshi, P. V. J . Org. Chem. 1993, 58, 1661-
1663.
(7) Von der Lippe, G.; Weber, H. Chem. Ber. 1985, 118, 3429-3437.
(8) Weber, H.; Von der Lippe, G. Chem. Ber. 1985, 118, 4086-4098.
(9) Vierhapper, F. W.; Eliel, E. L. J . Org. Chem. 1975, 40, 2729-
2734.
(10) Ho¨enel, M.; Vierhapper, F. W. J . Chem. Soc., Perkin Trans. 1
1980, 1933-1939.
(11) The intermediate 5,6,7,8-tetrahydroquinoline was intermit-
tently available commercially during this investigation.
(4) Sieburth, S. McN.; Hiel, G.; Lin, C.-H.; Kuan, D. P. J . Org. Chem.
1994, 59, 80-87.
(5) Sieburth, S. McN.; Madsen-Duggan, C. B.; Zhang, F. Tetrahedron
Lett. 2001, 42, 5155-5157.
(6) Sieburth, S. McN.; Chen, J .-l. J . Am. Chem. Soc. 1991, 113,
8163-8164.
10.1021/jo025565n CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/19/2002

3488 J . Org. Chem., Vol. 67, No. 10, 2002
Sch em e 1. Syn th esis of In ter m ed ia te 6
Zhu et al.
Sch em e 2. Cou p lin g of 6 w ith Lith iu m Rea gen t
13
stereoselectivity of the parent four-carbon photocycload-
dition.
P h otoch em istr y. 2-Pyridone photodimers are strained
polycyclic products,14 and when the photocycloaddition
is intramolecular with a four-carbon tether, the [4 + 4]
products have an additional portion of strain; the tether-
derived six-membered ring fused to the rigid polycyclic
pyridone dimer framework adopts a boat conformation
as its lowest energy option.15,16 In some cases, the strain
can be great enough that the photoproducts decompose
on silica gel chromatography. The photoreactions de-
scribed here, using a Pyrex-filtered medium-pressure
mercury lamp, were best run near 0 °C, and the yields
of chromatographically isolated photoproducts were gen-
erally moderate. Under these photochemical conditions,
only [4 + 4] products were formed in any significant
1
amounts, as determined by H NMR spectroscopy of the
crude photoreaction mixture. The ratio of the isolated
products paralleled the NMR-determined ratios.
Achiral 15 has the potential to form two diastereomeric
[4 + 4] products (cis and trans), but underwent photo-
cycloaddition to give only trans 16, Scheme 3. The 1H
NMR spectrum of photoproduct 16 has a characteristic
set of signals for the six protons surrounding the cyclooc-
tadiene ring; the sequence of coupling is readily followed
in the COSY spectrum (see Supporting Information). Also
characteristic of the trans isomers is the dispersion of
the alkene proton signals, presumably due to their
proximity to amide groups (see Figure 2). Cis isomers are
generally more labile than trans isomers and either are
not formed or undergo Cope rearrangement/photofrag-
mentation at the temperatures studied, behavior defined
for less strained congeners.17 Earlier studies6,18 are
consistent with these results; only trans pyridone pho-
toproducts have been isolated from reactions of four-
carbon-tethered pyridones. Hydrogenation of 16 gave the
saturated polycyclic product 17.
A more efficient alternative synthetic strategy began
with commercially available 2-fluoropyridine 8. Depro-
tonation of 8 with LDA and iodination to give 2-fluoro-
3-iodopyridine had been reported by Que´guiner,12 and
this reaction proved to be reproducibly high yielding.
Sonogashira coupling13 of this iodide with 3-butyne-1-ol
provided 11 in excellent yield. Saturation of the acetylene
and acetylation of the alcohol set the stage for hydrolysis
of the fluoropyridone. This was accomplished by N-
methylation with dimethyl sulfate, followed by treatment
with ethanolic triethylammonium acetate. Methanolysis
of ester 12 then gave alcohol 10. Preparation of 10 from
8 required six steps compared with five steps from quino-
line 7, but the overall yield from 8 was more than triple
that from 7. Introduction of the second pyridone of 1 was
anticipated by Swern oxidation of 10 to aldehyde 6.
The second pyridone was introduced using lithium
reagent 13 to give 14, albeit in modest yield, Scheme 2.
Hydrogenolysis of 14 with palladium-on-carbon gave the
desired alcohol 2 quantitatively. Extending the hydro-
genation time was found to give a substantial proportion
of deoxygenated 15. While this reaction was not opti-
mized for production of 15, the availability of this
photosubstrate was useful for defining the inherent
In agreement with our earlier report,6 photoreaction
of 2 gave products 1a and 1b, each of which could be
isolated and hydrogenated to give 18 and 19. The
diastereoselectivity of the photocycloaddition was influ-
enced by solvent. The two isomers are formed in nearly
(14) Sieburth, S. McN. In Advances in Cycloaddition; Harmata, M.,
Ed.; J AI: Greenwich, CT, 1999; Vol. 5, pp 85-118.
(15) Sieburth, S. McN. J . Chem. Soc., Chem. Commun. 1994, 1663-
1664.
(16) Sieburth, S. McN.; Chen, J .; Ravindran, K.; Chen, J .-l. J . Am.
Chem. Soc. 1996, 118, 10803-10810.
(12) Estel, L.; Marsais, F.; Que´guiner, G. J . Org. Chem. 1988, 53,
2740-2744.
(17) Sieburth, S. McN.; Lin, C.-H. J . Org. Chem. 1994, 59, 3597-
(13) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: New York, 1998; pp 203-
229.
3599.
(18) Sieburth, S. McN.; Ravindran, K. Tetrahedron Lett. 1994, 35,
3861-3864.

2-Pyridone Photochemistry and Reactivity
J . Org. Chem., Vol. 67, No. 10, 2002 3489
Sch em e 3. P h otocycloa d d ition of 15 a n d 2
leading to 1a , are shown in Figure 2. These structures
differ in the half-chair conformation of the tether and
were generated by holding C3 and C6 atoms of the
pyridones within 3.5 Å while minimizing the tether
conformations (Chem3D). Conformation 2-B is capable
of being stabilized by hydrogen bonding from the amide
nitrogen to the alcohol. Following cycloaddition, the new
tether-derived cyclohexane ring of trans-syn product 1a
can have the cyclohexane in either of two boat conforma-
tions, with 1a -B calculated to be lower in energy relative
to 1a -A by 1.2 kcal/mol (Chem3D). The crystal structure
of 1820 was found to be similar to the calculated structure
of 1a -B.
Am id e Hyd r olysis. Greico’s Boc-activation method
provides a very effective approach to secondary amide
hydrolysis;21 however, application of this procedure to
pyridone photoproducts has given mixed results. In cases
where the secondary amide nitrogen of the photoproducts
was relatively unhindered, N-derivatization and hydroly-
sis occurred smoothly;22 however, when the carbon at-
tached to the secondary amide nitrogen was fully sub-
stituted, introduction of an activating group proved to
be difficult, and Boc group introduction was fully unsuc-
cessful.23
Sch em e 4. Boc-Der iva tiza tion of Alcoh ols 18 a n d
19, F ollow ed by Meth a n olysis
For 18 and 19 the secondary amide nitrogen is quite
hindered. Nevertheless, treatment with di-tert-butyl di-
carbonate led, in each case, to a Boc derivative. Moreover,
dissolving these derivatives in methanol containing
potassium carbonate resulted, in both cases, in loss of
the tert-butyl group. For one of the isomers (22), the
methanolysis returned only the starting 19. For the other
Boc derivative (20), loss of the tert-butyl group was
accompanied by the appearance of a methyl ester. While
appearance of the methyl ester was not unexpected, loss
of the tert-butyl group was unexpected and suggested
participation of the nearby alcohol. The most likely
structure for this product was oxazolidinone 21. The IR
and 13C NMR data were fully consistent with this
structure, and the exact mass confirmed the identity.
A reasonable sequence of events leading to 21 is
derivatization of the alcohols of 18 and 19 to give 20 and
22, not the amide derivatives 23 and 24. Coupling of a
Boc group with the amide of a pyridone photoadduct in
an earlier study resulted in an upfield shift of the
carbonyl carbon in the 13C NMR spectrum by about 4
ppm,22 but an analogous change in the 13C NMR spectra
of 20 or 22 was not found. Hydrolysis of the amide in 20
must involve intramolecular delivery of the Boc group
to the amide nitrogen. It seems likely that this would
transiently result in intermediate 25. It is notable that
delivery of the Boc group by the alcohol requires that the
cyclohexane ring (see Figure 2) adopt the higher-energy
boat conformation with the Boc group in the flagpole
position. While this is clearly an energetically unfavor-
able option, a similar conformation has been observed
equal amounts, slightly favoring 1a , when methanol is
the photochemistry solvent. When the solvent is changed
to methylene chloride, isomer 1a comprises three-fourths
of the mixture. The product ratios shown in Scheme 3
were determined by NMR spectroscopy of the crude
photoreaction mixture, and the indicated yields are for
isolated products. The lower isolated yield for the meth-
ylene chloride reaction may reflect the effect of solvent
photodecomposition.19
The solvent effect, while relatively small, is consistent
with hydrogen bonding between the alcohol and the
adjacent amide nitrogen. Changing the solvent from
methylene chloride, where intramolecular hydrogen bond-
ing would be promoted, to methanol, would attenuate
intramolecular hydrogen bonding. Two photocycloaddi-
tion-conducive conformations of 2, 2-A and 2-B both
(20) Compound 18 crystallized in the monoclinic space group P21/n
with a ) 6.743 (1) Å, b ) 16.645 (2) Å, c ) 12.046 (3) Å, b ) 102.87
(2)°, V ) 1318.0 (5) Å3. The final least squares refinement using 882
unique reflections with I > 3s(I) gave R(Rw) ) 0.055 (0.044).
(21) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
(22) Sieburth, S. McN.; Rucando, D.; Lin, C.-H. J . Org. Chem. 1999,
64, 954-959. For
a related transformation, see: Klaver, W. J .;
Moolenaar, M. J .; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1988,
44, 3805-3818.
(19) Dilling, W. L.; Bredeweg, C. J .; Tefertiller, N. B. Environ. Sci.
Technol. 1976, 10, 351-356.
(23) McGee, K. F., J r.; Al-Tel, T. H.; Sieburth, S. McN. Synthesis
2001, 1185-1196.

3490 J . Org. Chem., Vol. 67, No. 10, 2002
Zhu et al.
F igu r e 2. Molecular models of 2, illustrating the potential for the alcohol to hydrogen bond to the amide nitrogen with the
tether in a half-chairlike conformation, leading to trans,syn product 1a . Pro-trans,anti conformational options are similar but are
not shown. Following cycloaddition, the tether-derived cyclohexane preferentially adopts a boat conformation, with 1a -A higher
in energy than 1a -B. A crystal structure of tetrahydro-1a (18) shows a conformation similar to that of calculated structure 1a -B.
for a tert-butyldimethylsilyl ether in crystal structures
Exp er im en ta l Section
of related molecules.18,24
4-(1,2-Dih yd r o-1-m et h yl-2-oxo-3-p yr id in yl)-b u t a n oic
Acid fr om 9. In a modification of the procedure described by
Weber,7 to a solution of K3Fe(CN)6 (41.6 g, 126 mmol) in 2 N
NaOH (180 mL) at 0 °C was added 1-methyl-5,6,7,8-tetrahy-
droquinolinium iodide 97 (3.47 g, 12.62 mmol) in 2 N NaOH
(126 mL) over 10 min. After 30 min of stirring, the mixture
was allowed to warm to room temperature for 45 min and then
heated with a 50 °C oil bath for another 3 h. The solution was
cooled, saturated with NaCl, and then extracted with CHCl3.
The aqueous phase was acidified to pH 4 with concentrated
H2SO4, saturated with NaCl, and then extracted with CHCl3.
The combined organic extracts were dried over MgSO4 and
concentrated to give a red-black solid. Flash chromatography
(60:40:1 toluene/acetone/formic acid) afforded the titled product
as a colorless solid (968 mg, 40%): Rf ) 0.28 (60:40:1 toluene/
acetone/formic acid); 1H NMR (CDCl3) δ 7.27-7.22 (m, 2H),
6.19 (t, 1H, J ) 6.7 Hz), 3.58 (s, 3H), 2.64 (t, 2H, J ) 7.2 Hz),
2.38 (t, 2H, J ) 7.2 Hz), 1.94 (quintet, 2H, J ) 7.2 Hz).
Meth yl 4-(1,2-Dih yd r o-1-m eth yl-2-oxo-3-p yr id in yl)-bu -
ta n oa te. To a solution of 4-(1,2-dihydro-1-methyl-2-oxo-3-
pyridinyl)-butanoic acid (967.8 mg, 4.96 mmol) in methanol
(20 mL) at room temperature was added concentrated H2SO4
(0.4 mL). After stirring for 18 h, the solution was neutralized
with methanolic sodium hydroxide, dried over Na2SO4, and
filtered through Celite. Concentration gave a yellow oil. Flash
chromatography (60:40:1 toluene/acetone/formic acid) afforded
the titled product as a colorless oil (988 mg, 95%): Rf ) 0.44
(60:40:1 toluene/acetone/formic acid); 1H NMR (CDCl3) δ 7.17
(m, 2H), 6.08 (t, 1H, J ) 6.9 Hz), 3.65 (s, 3H), 3.53 (s, 3H),
2.56 (t, 2H, J ) 7.8 Hz), 2.36 (t, 2H, J ) 7.8 Hz), 1.93 (quintet,
2H, J ) 7.8 Hz).
The reaction of secondary alcohols with di-tert-butyl
dicarbonate to form mixed carbonates is well precedented
in the work of Fre´chet25 and more recently that of
Hassner.26 Nevertheless, we are unaware of an amide
hydrolysis mediated in this way by a nearby alcohol. The
similarity of the amide methanolysis of 25 to cleavage of
other N-acylated oxazolidinones such as the removal of
the Evans chiral auxiliary27 is obvious; however, the
facility of this methanolysis is undoubtedly enhanced by
the relief of strain.
Con clu sion
A four-carbon tether between a pair of 2-pyridones
leads to a single trans adduct from intramolecular
photocycloaddition. When the tether has a hydroxyl
group, hydrogen bonding to a pyridone nitrogen results
in solvent-dependent diastereoselectivity for the cycload-
dition. The resulting secondary alcohol of the major
photoproduct can act to relay a Boc carbonyl group onto
the neighboring amide nitrogen, leading to a very facile
hydrolytic cleavage of the amide bond. This hydrolysis
chemistry provides a gentle method for manipulation of
the pyridone photoproducts that will prove to be useful
in the synthetic application of this versatile higher-order
cycloaddition.
3-(4-Hyd r oxybu tyl)-1-m eth yl-2(1H)-p yr id in on e 10. To
a solution of methyl 4-(1,2-dihydro-1-methyl-2-oxo-3-pyridinyl)-
butanoate (222 mg, 1.06 mmol) in THF (2 mL) at 0 °C was
added DIBAL (3.18 mL of a 1 M solution in hexame, 3.18
mmol). After the mixture was stirred for 2 h, methanol (1 mL)
was added and the mixture warmed to room temperature. A
saturated solution of Rochelle salt (2 mL) was added to the
mixture, and the aqueous phase was extracted with methylene
chloride. The combined organic phases were dried over Na2-
(24) Lee, Y. G.; McGee, K. F.; Chen, J . H.; Rucando, D.; Sieburth,
S. McN. J . Org. Chem. 2000, 65, 6676-6681.
(25) Houlihan, F.; Bouchard, F.; Frechet, J . M. J .; Willson, C. G.
Can. J . Chem. 1985, 63, 153-162.
(26) Basel, Y.; Hassner, A. J . Org. Chem. 2000, 65, 6368-6380.
(27) Evans, D. A.; Tedrow, J . S.; Shaw, J . T.; Downey, C. W. J . Am.
Chem. Soc. 2002, 124, 392-393.
(28) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.;
Mallet, M.; Godard, A.; Que´guiner, G. J . Org. Chem. 1993, 58, 7832-
7838.

2-Pyridone Photochemistry and Reactivity
J . Org. Chem., Vol. 67, No. 10, 2002 3491
SO4 and concentrated to give a yellow oil. Flash chromatog-
raphy (100:8 CH2Cl2/methanol) gave 10 as a colorless oil (159
mg, 83%): Rf ) 0.36 (100:8 CH2Cl2/methanol); 1H NMR
(CDCl3) δ 7.11 (d, 2H, J ) 6.0 Hz), 6.04 (t, 1H, J ) 6.6 Hz),
3.59 (t, 2H, J ) 5.5 Hz), 3.46 (s, 3H), 3.35 (s, 1H), 2.47 (t, 2H,
J ) 7.1 Hz), 1.60-1.52 (m, 4H); 13C NMR (CDCl3) δ 163.0,
136.1, 135.6, 133.3, 105.6, 61.9, 37.6, 32.0, 30.0, 24.3; IR (neat)
3394, 3087, 3011, 2934, 2861, 1646, 1583, 1560, 1407, 1062,
766 cm-1; exact mass calcd for C10H15NO2 181.1103, found
181.1099.
ethyl acetate (25 mL) was added 10% Pd/C (4.9 g), and the
mixture was stirred under 1 atm of hydrogen for 34 h.
Filtration and concentration of the filtrate gave a quantitative
yield of the title compound as a yellow oil: Rf ) 0.28 (1:1 ethyl
1
acetate/hexane); H NMR (CDCl3) δ 8.00 (d, 1H, J ) 4.7 Hz),
7.61-7.54 (m, 1H), 7.10-7.05 (m, 1H), 3.64 (t, 2H, J ) 6.0
Hz), 2.63 (t, 2H, J ) 7.4 Hz), 2.16 (s, 1H), 1.71-1.56 (m, 4H);
13C NMR (CDCl3) δ 163.4, 144.8, 140.8, 123.9, 121.4, 62.2, 32.0,
28.5, 25.7; IR (neat) 3394, 3011, 2934, 2861, 1646, 1583, 1560,
1407, 1223, 1062, 766 cm-1; exact mass calcd for C9H12FNO
169.0903, found 169.0901.
4-(1,2-Dih yd r o-1-m eth yl-2-oxo-3-p yr id in yl)-bu ta n a l 6.
To a solution of oxalyl chloride (0.348 mL, 3.92 mmol) in
methylene chloride (10 mL) at -78 °C was added DMSO (0.539
mL, 7.83 mmol). After gas evolution ceased, alcohol 10 (322.3
mL, 1.78 mmol) in methylene chloride (5 mL) was added
dropwise. The mixture was allowed to warm to -35 °C over
30 min, and then triethylamine (1.355 mL, 9.85 mmol) was
added. After the mixture was warmed to room temperature,
concentrated HCl (1 mL) was added. The organic phase was
washed with saturated NaHCO3 (10 mL), and the aqueous
phases were extracted with methylene chloride. The combined
organics were dried over Na2SO4 and concentrated to give a
yellow oil. Flash chromatography (60:40 CH2Cl2/acetone) af-
forded 6 as a colorless oil (264.2 mg, 87%): Rf ) 0.54 (60:40
4-(2-F lu or o-3-p yr id in yl)-bu tyl Aceta te. To a solution of
2-fluoro-3-(4-hydroxybutyl)-pyridine (220 mg, 1.30 mmol) and
DMAP (6.11 mg, 0.050 mmol) in methylene chloride (5 mL) at
room temperature were added acetic anhydride (0.245 mL,
2.60 mmol) and triethylamine (0.40 mL, 2.6 mmol). After the
mixture was stirred for 12 h, water (5 mL) was added and the
aqueous phase was extracted with methylene chloride. The
combined organics were dried over Na2SO4, filtered, and
concentrated to give a yellow oil. Flash chromatography (4:6
ethyl acetate/hexane) gave the title compound as a colorless
oil (249 mg, 91%): Rf ) 0.58 (1:1 ethyl acetate/hexane); 1H
NMR (CDCl3) δ 8.04 (d, 1H, J ) 4.4 Hz), 7.61-7.55 (m, 1H),
7.11-7.08 (m, 1H), 4.08 (t, 2H, J ) 5.6 Hz), 2.67-2.63 (t, 2H,
J ) 6.8 Hz), 2.03 (s, 3H), 1.68-1.66 (m, 4H); 13C NMR (CDCl3)
δ 171.1, 161.6, 145.1, 144.7, 123.6, 121.4, 63.9, 28.4, 28.1, 25.9,
20.9; IR (neat) 3063, 2952, 2868, 1736, 1604, 1578, 1434, 1366,
1243, 1046, 801 cm-1; exact mass calcd for C11H14FNO2
211.1009, found 211.1006.
1
CH2Cl2/acetone); H NMR (CDCl3) δ 9.69 (m, 1H), 7.14-7.09
(m, 2H), 6.02 (t, 1H, J ) 6.9 Hz), 3.46 (s, 3H), 2.51-2.37 (m,
4H), 1.86 (quintet, 2H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 202.3,
162.7, 136.4, 136.0, 132.0, 105.3, 43.2, 37.5, 30.3, 20.7; IR (neat)
3016, 2937, 2867, 2735, 1714, 1644, 1562, 1110, 769 cm-1; exact
mass calcd for C10H13NO2 179.0947, found 179.0946.
4-(1,2-Dih yd r o-1-m eth yl-2-oxo-3-p yr id in yl)-bu tyl Ac-
eta te (12). To a solution of 4-(2-fluoro-3-pyridinyl)-butyl
acetate (1.453 g, 6.88 mmol) in chloroform (10 mL) at 0 °C
was added dimethyl sulfate (3.9 mL, 41.3 mmol) over 4 min.
The reaction mixture was heated to reflux for 15 h and cooled
to room temperature, and a mixture of triethylamine/acetic
acid/ethanol (3:2:2, 47.5 mL) was added. After the mixture was
refluxed for an additional 1 h, water (5 mL) was added. The
aqueous phase was extracted with methylene chloride; the
combined organics were dried over Na2SO4 and concentrated
to give a yellow oil. Flash chromatography (100:5 methylene
chloride/methanol) gave 12 as a colorless oil (1.276 g, 83%):
Rf ) 0.60 (100:8 methylene chloride/methanol); 1H NMR
(CDCl3) δ 7.09 (m, 2H), 6.00 (t, 1H, J ) 6.6 Hz), 3.99 (t, 2H, J
) 5.7 Hz), 3.45 (s, 3H), 2.46 (t, 2H, J ) 6.6 Hz), 1.94 (s, 3H),
1.59-1.54 (m, 4H); 13C NMR (CDCl3) δ 170.9, 162.7, 135.9,
135.7, 132.8, 105.2, 64.2, 37.5, 30.2, 28.2, 24.4, 20.8; IR (neat)
3120, 3077, 2951, 2867, 1732, 1649, 1589, 1560, 1247, 1037,
764 cm-1; exact mass calcd for C12H17NO3 223.1209, found
223.1209.
3-(4-H yd r oxyb u t yl)-1-m et h yl-2(1H )-p yr id in on e (10)
fr om 12. To a solution of 12 (638.0 mg, 2.86 mmol) in a
mixture of methanol (20 mL) and water (2 mL) was added K2-
CO3 (591 mg, 4.29 mmol). After 1 h of stirring, the mixture
was filtered, concentrated, and extracted with methylene
chloride. The organic phase was dried over Na2SO4 and
concentrated to give a pale yellow oil. Flash chromatography
(10:1 methylene chloride/methanol) gave 10 as a colorless oil
(492.9 mg, 95%).
2-F lu or o-3-iod op yr id in e.12 To a solution of diisopropy-
lamine (7 mL, 50 mmol) in THF (200 mL) at -20 °C was added
n-BuLi (20 mL of a 2.5 M solution in hexane, 50 mmol). After
stirring for 30 min, the mixture was cooled to -78 °C and a
solution of 2-fluoropyridine (4.39 mL, 0.050 mmol) in THF (50
mL) was added over 10 min. The resulting yellow suspension
was stirred for 4 h at -78 °C at which time a solution of iodine
(12.7 g, 50 mmol) in THF (45 mL) was added. After stirring
for 1 h at -78 °C, a mixture of H2O (10 mL) and THF (50 mL)
was added. After the mixture was warmed to 0 °C, additional
water (50 mL) was added, followed by solid sodium thiosulfate.
The aqueous phase was extracted with ether; the combined
organics were dried over Na2SO4 and concentrated to give a
brown oil that was purified by Kugelrohr distillation to give
the 2-fluoro-3-iodopyridine as a colorless solid (10.1 g, 91%).
Recrystallization from hexane/ether (50:1) gave an analytical
sample: Rf ) 0.61 (1:6 ethyl acetate/hexane); mp ) 42-43 °C
1
(lit.12 43 °C); H NMR (CDCl3) δ 8.15 (m, 2H), 6.95 (m, 1H);
13C NMR (CDCl3) δ 145.7, 142.9, 142.7, 118.3, 118.2; IR (KBr)
3438, 2958, 2920, 1578, 1559, 1427, 1406, 1251, 1237 cm-1
.
When an excess of LDA was used, 2-fluoro-3,4-diiodopyri-
dine28 could be isolated as from the residue of the Kugelrohr
distillation: Rf ) 0.63 (1:6 ethyl acetate/hexane); mp ) 107-
1
109 °C (lit.28 114 °C); H NMR (CDCl3) δ 7.86 (d, 1H, J ) 5.0
Hz), 7.66 (dd, 1H, J ) 0.6, 5.0 Hz); 13C NMR (CDCl3) δ 142.6,
142.4, 127.74, 127.68, 95.5; IR (KBr) 1569, 1551, 1516, 1426,
1365 cm-1. Anal. Calcd for C5H2FI2N: C, 17.21; H 0.85; N, 4.01.
Found: C, 17.39; H, 0.65; N, 3.97.
4-(2-F lu or o-3-p yr id in yl)-3-bu tyn -1-ol (11). To a suspen-
sion of 2-fluoro-3-iodopyridine (25.5 g, 114 mmol), (PPh3)2PdCl2
(3.37 g, 4 mol %), and CuI (430 mg, 2 mol %) in triethylamine
(450 mL) at 0 °C was added 3-butyn-1-ol (9.52 mL, 126 mmol).
After stirring for 9 h, water (500 mL) was added and the
aqueous phase was extracted with ether. The combined
organics were washed twice with 10% HCl, dried over Na2-
SO4, and concentrated to give a black oil. Kugelrohr distillation
gave 11 as a colorless oil (17.9 g, 95%): Rf ) 0.29 (4:6 ethyl
3-[4-(6-Ben zyloxy-2-pyr idin yl)-4-h ydr oxybu tyl]-1-m eth -
yl-2(1H)-p yr id in on e (14). To a solution of 6-bromo-2-benzy-
loxypyridine (4.27 g, 16.2 mmol) in THF (50 mL) at -78 °C
was added n-butyllithium (6.03 mL of a 2.5 M solution in
hexane, 15.1 mmol) over 5 min. The solution was stirred for
40 min, and then aldehyde 6 (1.93 g, 10.8 mmol) in THF (30
mL) was added slowly over 20 min. The mixture was stirred
for 1 h and quenched with saturated NH4Cl (4 mL) and the
aqueous phase extracted with methylene chloride. The com-
bined organics were dried over Na2SO4 and concentrated to
give a brown oil. Flash chromatography (60:40:8 ethyl acetate/
hexane/methanol) afforded 14 as pale yellow oil (1.43 g, 38%):
Rf ) 0.57 (60:40:8 ethyl acetate/hexane/methanol); 1H NMR
(CDCl3) δ 7.56 (t, 1H, J ) 7.8 Hz), 7.45-7.26 (m, 5H), 7.16 (d,
2H, J ) 6.6 Hz), 6.83 (d, 1H, J ) 7.1 Hz), 6.67 (d, 1H, J ) 8.0
Hz), 6.08 (t, 1H, J ) 6.9 Hz), 5.38 (s, 2H), 4.68 (m, 1H), 3.90
(d, 1H, J ) 6.0 Hz), 3.53 (s, 3H), 2.61-2.54 (m, 2H), 1.88-
1
acetate/hexane); H NMR (CDCl3) δ 8.10 (d, 1H, J ) 4.7 Hz),
7.78 (m, 1H), 7.12 (m, 1H), 3.84 (q, 2H, J ) 6.3 Hz), 2.72 (t,
2H, J ) 6.3 Hz), 2.24 (s, 1H); 13C NMR (CDCl3) δ 164.3, 146.1,
143.6, 121.0, 107.8, 94.1, 74.0, 60.8, 23.9; IR (neat) 3377, 3072,
2946, 2866, 2237, 1602, 1438, 1255, 1048 cm-1; exact mass
calcd for C9H8FNO 165.0590, found 165.0591.
2-F lu or o-3-(4-h yd r oxybu tyl)-p yr id in e. To a solution of
11 (17.94 g, 109 mmol) in a mixture of ethanol (25 mL) and

3492 J . Org. Chem., Vol. 67, No. 10, 2002
Zhu et al.
1.68 (m, 4H); 13C NMR (CDCl3) δ 163.0, 162.6, 160.1, 139.2,
137.2, 135.9, 135.6, 133.3, 128.3, 127.8, 127.7, 112.9, 109.2,
105.4, 72.5, 67.5, 37.8, 37.6, 30.2, 24.0; IR (neat) 3384, 3064,
3031, 2940, 2865, 1647, 1576, 1448, 1022, 753 cm-1; exact mass
calcd for C22H24N2O3 364.1781, found 364.1789.
7.2 Hz), 6.00 (dd, 1H, J ) 8.4, 1.5 Hz), 4.17 (ddd, 1H, J ) 9.6,
7.2, 1.2 Hz), 4.03-3.99 (m, 1H), 3.50 (ddd, 1H, J ) 9.6, 7.2,
1.2 Hz), 2.77 (s, 3H), 2.36-2.26 (m, 1H), 2.06-1.70 (m, 5H).
An ti Isom er Com p ou n d 1b: mp ) 204-207 °C;6 Rf ) 0.36
1
(10:1 CH2Cl2/methanol); H NMR (CD3OD) δ 6.70 (dd, 1H, J
3-[4-(1,6-Dih yd r o-6-oxo-2-p yr id in yl)-4-h yd r oxybu tyl]-
1-m eth yl-2(1H)-p yr id in on e (2) a n d 3-[4-(1,6-Dih yd r o-6-
oxo-2-p yr id in yl)-bu tyl]-1-m eth yl-2(1H)-p yr id in on e (15).
To a solution of 14 (1.32 g, 3.76 mol) in ethanol (20 mL) was
added 10% Pd/C (412.3 mg). After 20 h of stirring at room
temperature under 1 atm of hydrogen, the mixture was
filtered. Concentration gave a pale yellow oil. Flash chroma-
tography (10:1 CH2Cl2/methanol) gave 2 as a colorless oil
(589.6 mg, 45%) and 15 (214.3 mg, 17%) as a colorless solid.
Com p ou n d 2:6 Rf ) 0.25 (100:8 CH2Cl2/methanol); 1H NMR
(CD3OD) δ 7.56-7.48 (m, 2H), 7.37 (d, 1H, J ) 6.6 Hz), 6.40-
6.27 (m, 3H), 4.58 (t, 1H, J ) 5.4 Hz), 3.56 (s, 3H), 2.55 (t, 2H,
J ) 6.6 Hz) 1.75-1.64 (m, 4H).
Com p ou n d 15: Rf ) 0.38 (100:8 CH2Cl2/methanol); mp )
111.7-112.9 °C; 1H NMR (CD3OD) δ 7.73 (dd, 1H, J ) 9.0,
6.9 Hz), 7.16 (d, 2H, J ) 6.9 Hz), 6.37 (d, 1H, J ) 9.3 Hz),
6.08-6.00 (m, 2H), 3.54 (s, 3H), 2.65-2.53 (m, 4H), 1.72-1.61
(m, 4H); 13C NMR (CD3OD) δ 165.6, 163.1, 150.0, 141.5, 136.2,
135.7, 133.1, 116.8, 105.6, 104.9, 37.8, 32.6, 29.9, 28.2, 27.6;
IR (neat) 3418, 3287, 3124, 2935, 2861, 1646, 1617, 1581, 1561,
1455 cm-1; exact mass calcd for C15H18N2O2 258.1364, found
258.1371.
) 8.7, 1.2 Hz), 6.61 (dd, 1H, J ) 8.7, 6.6 Hz), 6.28 (dd, 1H, J
) 8.7, 6.6 Hz), 5.80 (dd, 1H, J ) 8.7, 1.2 Hz), 4.14 (ddd, 1H, J
) 9.6, 6.6, 1.2 Hz), 3.97-3.92 (m, 1H), 3.48 (ddd, 1H, J ) 9.6,
6.6, 1.5 Hz), 2.76 (s, 3H), 2.46-2.31 (m, 1H), 2.01-1.67 (m,
5H).
(3r,4â,6râ,10r,10rr)-4,5,7,8,9,10,11,12,13,14-Deca h yd r o-
10-h yd r oxy-5-m et h yl-3,10a :4,6a -d iet h a n o-1,5-b en zod ia -
zocin e-2,6(1H,3H)-d ion e (18). To a solution of 1a (32.8 mg,
0.12 mmol) in methanol (4 mL) was added 10% Pd/C (27.1 mg).
After stirring for 20 h at room temperature under 1 atm of
hydrogen, the mixture was filtered through Celite. Concentra-
tion gave a pale yellow oil. Flash chromatography (10:1 CH2-
Cl2/methanol) gave 186 (29.6 mg, 89%) as a colorless solid: Rf
) 0.48 (10:1 CH2Cl2/methanol); mp ) 232.5-233.1 °C; 1H NMR
(CD3OD) δ 4.02 (m, 1H), 3.68 (t, 1H, J ) 6.6 Hz), 3.05 (s, 3H),
2.94 (m, 1H), 2.49-2.40 (m, 1H), 2.16-1.37 (m, 13H); 13C NMR
(CD3OD) δ 179.8, 178.3, 73.1, 62.2, 58.0, 51.8, 46.3, 37.5, 31.5,
29.8, 29.5, 25.0, 24.0, 22.2, 16.2; IR (neat) 3388, 2948, 2880,
1727, 1650, 1643, 1469, 1329, 731 cm-1
.
(3r,4â,6râ,10â,10rr)-4,5,7,8,9,10,11,12,13,14-Deca h yd r o-
10-h yd r oxy-5-m et h yl-3,10a :4,6a -d iet h a n o-1,5-b en zod ia -
zocin e-2,6(1H,3H)-d ion e (19). To a solution of 1b (29.2 mg,
0.11 mmol) in methanol (3 mL) was added 10% Pd/C (19.5 mg).
After stirring for 20 h at room temperature under 1 atm of
hydrogen, the mixture was filtered through Celite. Concentra-
tion gave a pale yellow oil. Flash chromatography (10:1 CH2-
Cl2/methanol) gave 196 (26.9 mg, 91%) as colorless solid: Rf )
0.39 (10:1 CH2Cl2/methanol); mp ) 257.2-258.5 °C; 1H NMR
(CD3OD) δ 4.00 (ddd, 1H, J ) 11.1, 6.4, 1.2 Hz), 3.86 (dd, 1H,
J ) 11.4, 5.7 Hz), 3.06 (s, 3H), 2.91 (ddd, 1H, J ) 11.1, 5.1,
1.8 Hz), 2.32-1.37 (m, 14H); 13C NMR (CD3OD) δ 179.7, 178.5,
70.4, 63.7, 58.3, 52.4, 46.2, 37.4, 32.0, 25.3, 25.0, 24.5, 21.8,
17.5; IR (neat) 3417, 2955, 2852, 1642, 1469, 1450, 1210, 799
cm-1; exact mass calcd for C15H22N2O3 278.1625, found 278.1642.
(3r,4â,6râ,10r,10rr)-4,5,7,8,9,10,11,12,13,14-Deca h yd r o-
10-[[(1,1-d im eth yleth oxy)ca r bon yl]oxy]-5-m eth yl-3,10a :
4,6a -d ieth a n o-1,5-ben zod ia zocin e-2,6(1H,3H)-d ion e (20).
To a solution of 18 (102.3 mg, 0.37 mmol) in methylene chloride
(10 mL) were added di-tert-butyl dicarbonate (200.8 mg, 0.93
mmol), DMAP (7 mg), and triethylamine (0.14 mL, 0.93 mmol)
at room temperature. After the mixture was stirred for 15 h,
water (2 mL) was added and the aqueous phase was extracted
with methylene chloride. The combined organic phases were
dried over Na2SO4 and concentrated to give a yellow oil. Flash
chromatography (70:30:8.3 ethyl acetate/hexane/methanol)
gave 20 as a colorless solid (100.9 mg, 72%): Rf ) 0.35 (70:
30:8.3 ethyl acetate/hexane/methanol); 1H NMR (CD3OD) δ
4.68-4.64 (m, 1H), 4.05-3.99 (m, 1H), 3.06 (s, 3H), 2.97-2.93
(m, 1H), 2.54-2.44 (m, 1H), 2.24-1.32 (m, 22H); 13C NMR
(CD3OD) δ 179.5, 177.6, 154.2, 83.6, 78.5, 61.6, 58.0, 52.2, 46.3,
37.5, 31.2, 29.9, 29.6, 27.9, 24.9, 21.8, 20.7, 15.8; IR (KBr) 2958,
2883, 1738, 1675, 1649, 1281, 1255, 1160 cm-1; exact mass
calcd for C20H31N2O5 379.2249, found 379.2233.
(3r,4â,6râ,10rr)-4,5,7,8,9,10-H exa h yd r o-5-m et h yl-3,-
10a :4,6a -d iet h en o-1,5-b en zod ia zocin e-2,6(1H ,3H )-d ion e
(16). Dry nitrogen was bubbled for 15 min through a methanol
(2.4 mL) solution of bis-2-pyridone 15 (30.0 mg, 0.12 mmol,
50 mM) in a quartz tube. The solution was cooled to 10 °C
and irradiated for 22 h with a Pyrex-filtered medium-pressure
mercury lamp. Concentration and flash chromatography (7:
3:1 ethyl acetate/hexane/methanol) gave 16 (10.0 mg, 33%) as
a
colorless solid: Rf ) 0.26 (7:3:1 ethyl acetate/hexane/
methanol); mp ) 158.5-159.5 °C; 1H NMR (CDCl3) δ 6.64 (dd,
1H, J ) 8.4, 6.9 Hz), 6.30 (dd, 1H, J ) 8.4, 1.2 Hz), 6.23 (dd,
1H, J ) 8.4, 6.9 Hz), 6.03 (dd, 1H, J ) 8.4, 1.5 Hz), 4.15 (ddd,
1H, J ) 9.9, 6.9, 1.5 Hz), 3.47 (ddd, 1H, J ) 9.9, 6.9, 1.5 Hz),
2.77 (s, 3H), 2.29 (m, 1H), 1.97-1.69 (m, 7H); 13C NMR (CD3-
OD) δ 180.6, 179.2, 142.9, 138.4, 134.3, 128.9, 61.2, 59.9, 57.3,
52.5, 36.2, 31.4, 26.9, 15.6, 14.9; IR (neat) 3058, 2926, 2877,
1640, 1646, 1398, 798 cm-1; exact mass calcd for C15H18N2O2
258.1328, found 258.1372.
(3r,4â,6râ,10rr)-4,5,7,8,9,10,11,12,13,14-Deca h yd r o-5-
m eth yl-3,10a:4,6a-dieth an o-1,5-ben zodiazocin e-2,6(1H,3H)-
d ion e (17). To a solution of 16 (24.0 mg, 0.093 mmol) in
methanol (4 mL) was added 10% Pd/C (40 mg). After stirring
for 20 h under 1 atm of hydrogen, the mixture was filtered
through Celite. Concentration gave a pale yellow oil. Flash
chromatography (7:3:1 ethyl acetate/hexane/methanol) gave 17
(29.6 mg, 88%) as a colorless solid: Rf ) 0.26 (7:3:1 ethyl
acetate/hexane/methanol); mp ) 219.6-221.0 °C; 1H NMR
(CD3OD) δ 4.00 (ddd, 1H, J ) 11.1, 6.6, 1.5 Hz), 3.05 (s, 3H),
2.91 (m, 1H), 2.11-1.52 (m, 16H); 13C NMR (CD3OD) δ 179.5,
178.8, 59.6, 58.1, 50.9, 46.4, 27.4, 36.5, 33.6, 31.1, 30.8, 25.1,
22.2, 16.4, 15.3; IR (KBr) 3423, 2958, 2877, 1670, 1646, 1467,
1406 cm-1; exact mass calcd for C15H22N2O2 262.1676, found
262.1683.
Oxa zolid in on e 21. To a solution of 20 (91.7 mg, 0.24 mmol)
in methanol (25 mL) was added K2CO3 (400.3 mg, 2.88 mmol).
After stirring for 2 h, the mixture was filtered and concen-
trated. Saturated NH4Cl (3 mL) was added, and the aqueous
phase was extracted with methylene chloride. The combined
organic phases were dried over Na2SO4 and concentrated to
give a colorless oil. Flash chromatography (70:30:9 ethyl
acetate/hexane/methanol) gave 21 (30.6 mg, 50%) as a colorless
solid and 20 (7.0 mg, 10%); Rf ) 0.43 (70:30:9 ethyl acetate/
(3r,4â,6râ,10r,10rr)-4,5,7,8,9,10-Hexah ydr o-10-h ydr oxy-
5-m e t h yl-3,10a :4,6a -d ie t h e n o-1,5-b e n zod ia zocin e -2,6-
(1H,3H)-d ion e (1a ) a n d (3r,4â,6râ,10â,10rr)-4,5,7,8,9,10-
Hexa h yd r o-10-h yd r oxy-5-m eth yl-3,10a :4,6a -d ieth en o-1,5-
ben zod ia zocin e-2,6(1H,3H)-d ion e (1b). Dry nitrogen was
bubbled for 15 min through a solution of methanol (22.7 mL)
containing bis-2-pyridone 2 (311 mg, 1.14 mmol, 50 mM) in a
quartz tube. The solution was irradiated for 37 h at 10 °C using
a Pyrex-filtered medium-pressure mercury lamp. Concentra-
tion of the solution and Flash chromatography (10:1 CH2Cl2/
methanol) gave trans,syn 1a (107.7 mg, 35%) and trans,anti
1b (86.1 mg 28%), both as colorless solids.
1
hexane/methanol); mp ) 236.5-237.5 °C; H NMR (CD3OD)
δ 4.28-4.25 (m, 1H), 4.09-4.06 (m, 1H), 3.69 (s, 3H), 2.96 (s,
3H), 2.89 (m, 1H), 2.17-1.54 (m, 14H); 13C NMR (CD3OD) δ
177.3, 174.8, 161.3, 86.5, 66.2, 59.3, 52.5, 47.7, 46.5, 37.6, 35.1,
24.2, 32.3, 26.0, 21.7. 19.2, 18.8; IR (neat) 2939, 2877, 1745,
1641, 1379, 1299, 1250, 1054, 992, 733 cm-1; exact mass calcd
for C17H24N2O5 336.1679, found 336.1682.
Syn Isom er Com p ou n d 1a : mp ) 213 °C;6 Rf ) 0.30 (10:1
CH2Cl2/methanol); 1H NMR (CD3OD) δ 6.66 (dd, 1H, J ) 8.8,
7.2 Hz), 6.39 (dd, 1H, J ) 8.4, 1.5 Hz), 6.26 (dd, 1H, J ) 8.4,

2-Pyridone Photochemistry and Reactivity
J . Org. Chem., Vol. 67, No. 10, 2002 3493
(3r,4â,6râ,10â,10rr)-4,5,7,8,9,10,11,12,13,14-Deca h yd r o-
10-[[(1,1-d im eth yleth oxy)ca r bon yl]oxy]-5-m eth yl-3,10a :
4,6a -d ieth a n o-1,5-ben zod ia zocin e-2,6(1H,3H)-d ion e (22).
To a solution of 19 (17.9 mg, 0.064 mmol) in methylene chloride
(5 mL) at room temperature were added di-tert-butyl dicar-
bonate (35.2 mg, 0.16 mmol), DMAP (5 mg), and triethylamine
(0.10 mL, 0.67 mmol). After the mixture was stirred for 7 h,
water (1 mL) was added and the aqueous phase was extracted
with methylene chloride. The combined organic phases were
dried over Na2SO4 and concentrated to give a yellow oil. Flash
chromatography (20:1 methylene chloride/methanol) gave 22
as a colorless solid (24.0 mg, 99%): Rf ) 0.61 (10:1 methylene
chloride/methanol); 1H NMR (CDCl3) δ 6.32 (s, 1H), 4.95-4.89
(m, 1H), 3.87-3.81 (m, 1H), 3.07 (s, 3H), 2.96-2.92 (m, 1H),
2.44-1.48 (m, 23H); 13C NMR (CD3OD) δ 179.4, 177.9, 154.7,
83.4, 76.8, 62.5, 58.2, 52.7, 46.1, 37.4, 31.8, 31.4, 28.0, 26.0,
25.1, 21.8, 21.5, 16.9; IR (neat) 2954, 2883, 1739, 1675, 1650,
1282, 1257, 1162, 1090, 733 cm-1; exact mass calcd for
C
20H30N2O5 378.2417, found 378.2153.
Ack n ow led gm en t. Support of this work by the
National Institutes of Health is gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Proton NMR and
COSY spectra for new compounds and crystallographic data
for 18. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O025565N