A One-Pot Condensation of Pyrones and Enals. Synthesis of 1H,7H-5a,6,8,9-Tetrahydro-1-oxopyrano[4,3-6][1]benzopyrans

Article abstract of DOI:10.1021/jo970642d

Condensation of various 6-substituted 4-hydroxypyrones 1 with 1-cyclohexenecarboxaldehydes in the presence of L-proline in ethyl acetate gave high yields of substituted 1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-6][1]benzopyrans. The reaction presumably oc

Full text of DOI:10.1021/jo970642d

6888
J . Org. Chem. 1997, 62, 6888-6896
A On e-P ot Con d en sa tion of P yr on es a n d En a ls. Syn th esis of
1H,7H-5a ,6,8,9-Tetr a h yd r o-1-oxop yr a n o[4,3-b][1]ben zop yr a n s
Duy H. Hua,* Yi Chen, Hong-Sig Sin, Maria J . Maroto, Paul D. Robinson,1
Steven W. Newell,2 Elisabeth M. Perchellet,2 J ames B. Ladesich,2 J onathan A. Freeman,2
J ean-Pierre Perchellet,2 and Peter K. Chiang3
Department of Chemistry, Kansas State University, Manhattan, Kansas 66506
Received April 10, 1997X
Condensation of various 6-substituted 4-hydroxypyrones 1 with 1-cyclohexenecarboxaldehydes in
the presence of L-proline in ethyl acetate gave high yields of substituted 1H,7H-5a,6,8,9-tetrahydro-
1-oxopyrano[4,3-b][1]benzopyrans. The reaction presumably occurs via the 1,2-addition of the pyrone
with the aldehyde followed by dehydration and then cyclization through a 6Π electrocyclic process.
A remarkable asymmetric induction was obtained from a stereogenic center (C4) of the cyclohex-
enecarboxaldehyde [such as (S)-perillaldehyde] to provide only the C5a,7-trans tricyclic pyrone
products. On the other hand, condensation of 3-(formyloxy)- or 3-hydroxy-2-methyl-1-cyclohexene-
carboxaldehydes with pyrones 1 gave mixtures of C5a,6-cis and -trans products. Several of the
tricyclic pyrones strongly inhibit acetylcholinesterase activity, DNA synthesis, and tumor cell growth
in vitro.
I. In tr od u ction
the condensation of 6-substituted 4-hydroxy-2-pyrones 1
with substituted 1-cyclohexenecarboxaldehydes 2-5 in
the presence of an amino acid (such as L-proline). These
tricyclic pyrones were formed presumably through 1,2-
addition reaction followed by in situ ring closure. In the
ring closure reactions, asymmetric induction was ob-
served from a stereogenic center (C4) in the carboxalde-
hyde. These tricyclic compounds have not been previ-
ously reported and possess a variety of important biological
activities. Herein, the condensation reactions are re-
ported and some of the biological testing results are
summarized.
Condensation reactions of 4-hydroxy-6-methyl-2-py-
rone (1A)4 and 4-hydroxycoumarin5 with acyclic R,â-
unsaturated enones and enals provided 1,4-addition
products (Michael adducts; attack from C3 of pyrones)
as the predominant4 or sole5 products; 1,2-addition
products were formed as the minor products in few of
the reactions.4a,b Acetic acid and piperidine in ethanol4
or pyridine5 were used as reagents and solvent in these
reactions. Reaction with cyclic enals has not been
reported. In our studies of the synthesis of biologically
active compounds and studies toward total synthesis of
natural products such as pyripyropenes6 and arisugacin,7
various substituted tricyclic pyrones were synthesized via
II. Resu lts a n d Discu ssion
Despite the finding that the 1,4-adducts were the
predominant products in the condensation of pyrone 1A
with (E)-2-butenal and cinnamaldehyde,4b treatment of
1-cyclohexenecarboxaldehyde (2) with 1 equiv of 1A and
0.5 equiv of L-proline in ethyl acetate at 70 °C for 24 h
provided a 76% yield of tricyclic pyrone 6A (Scheme 1).
Presumably, 6A was formed through the 1,2-addition of
the pyrone onto the enal followed by dehydration and ring
closure via the 6Π electrocyclic process (i.e., 7; in which
the catalyst, L-proline, is not involved).8 The structure
of 6A was firmly established by a single-crystal X-ray
analysis (Figure 1).9 The crystal has a centric space
group, triclinic P1h, and is racemic (the optical rotation
of 6A is zero). Although no intermediate was detected
when the reaction was followed by 1H NMR spectroscopy,
the formation of a racemic product suggests that a
X Abstract published in Advance ACS Abstracts, August 15, 1997.
(1) Department of Geology, Southern Illinois University at Carbon-
dale, Carbondale, IL 62901. Author to whom correspondence concern-
ing the X-ray crystal structure determination should be addressed.
(2) Anti-Cancer Drug Laboratory, Department of Biology, Ackert
Hall, Kansas State University, Manhattan, KS 66506-4901.
(3) Department of Applied Biochemistry, Walter Reed Army Insti-
tute of Research, Washington DC 20307-5100.
(4) With enones and enals: (a) de March, P.; Moreno-Manas, M.;
Pleixats, R.; Roca, J . L. J . Heterocycl. Chem. 1984, 21, 1369-1370 and
references cited therein. (b) de March, P.; Moreno-Manas, M.; Casado,
J .; Pleixats, R.; Roca, J . L.; Trius, A. J . Heterocycl. Chem., 1984, 21,
85-89. With aldehydes: (c) Cervera, M.; Moreno-Manas, M.; Pleixats,
R. Tetrahedron 1990, 46, 7885-7892. (d) Moreno-Manas, M.; Papell,
E.; Pleixats, R.; Ribas, J .; Virgili, A. J . Heterocycl. Chem. 1986, 23,
413-416. (e) Moreno-Manas, M.; Pleixats, R. Synthesis 1984, 430-
431. (f) de March, P.; Moreno-Manas, M.; Roca, J . L. J . Heterocycl.
Chem. 1984, 21, 1371-1372. (g) de March, P.; Moreno-Manas, M.; Pi,
R.; Trius, A. J . Heterocycl. Chem. 1982, 19, 335-336.
(5) With enones: (a) Hutchinson, D. W.; Tomlinson, J . A. Tetrahe-
dron Lett. 1968, 48, 5027-5028. (b) Ikawa, M.; Stahmann, M. A.; Link,
K. P. J . Am. Chem. Soc. 1944, 66, 902-909. (c) Seidman, M.; Link, K.
P. J . Am. Chem. Soc. 1952, 74, 1885-1886. (d) Seidman, M.; Robertson,
D. N.; Link, K. P. J . Am. Chem. Soc. 1950, 72, 5193-5194.
(6) Isolation: (a) Omura, S.; Tomoda, H.; Kim, Y. K.; Nishida, H. J .
Antibiot. 1993, 46, 1168-1169. (b) Tomoda, H.; Kim, Y. K.; Nishida,
H.; Masuma, R.; Omura, S. J . Antibiot. 1994, 47, 148-153. Structure
of (+)-pyripyropene A: (c) Tomoda, H.; Nishida, H.; Kim, Y. K.; Obata,
R.; Sunazuka, T.; Omura, S.; Bordner, J .; Guadliana, M.; Dormer, P.
G.; Smith, A. B., III. J . Am. Chem. Soc. 1994, 116, 12097-12098.
Synthesis of (+)-pyripyropene A: (d) Nagamitsu, T.; Sunazuka, T.;
Obata, R.; Tomoda, H.; Tanaka, H.; Harigaya, Y.; Omura, S.; Smith,
A. B., III. J . Org. Chem. 1995, 60, 8126-8127. Synthesis of (()-
GERI-BP001: (e) Parker, K. A.; Resnick, L. J . Org. Chem. 1995, 60,
5726-5728. Synthesis of (+)-pyripyropene E: (f) Smith, A. B., III;
Kinsho, T.; Sunazuka, T.; Omura, S. Tetrahedron Lett. 1996, 37, 6461-
6464.
(7) Isolation and biological activities: (a) Omura, S.; Kuno, F.;
Otoguro, Sunazuka, T.; Shiomi, K.; Masuma, R.; Iwai, Y. J . Antibiot.
1995, 48, 745-746. (b) Kuno, F.; Otoguro, K.; Shiomi, K.; Iwai, Y.;
Omura, S. J . Antibiot. 1996, 49, 742-747.
(8) (a) Shamma, M.; Hwang, D. Tetrahedron 1974, 30, 2279-2282.
(b) Corey, E. J .; J ardine, P. D. S.; Rohloff, J . C. J . Am. Chem. Soc.
1988, 110, 3672-3673.
(9) The asymmetric unit contains two nearly identical molecules
with a ) 8.8552(16) Å, b ) 18.977(4) Å, c ) 6.7869(11) Å, and R factor
) 0.0450. The author has deposited atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
S0022-3263(97)00642-7 CCC: $14.00 © 1997 American Chemical Society

One-Pot Condensation of Pyrones and Enals
J . Org. Chem., Vol. 62, No. 20, 1997 6889
Sch em e 2
F igu r e 1. ORTEP drawing of X-ray crystallographically
determined structure of 6A. Displacement ellipsoids are shown
at the 30% probability level.
Sch em e 1
at 0 °C for 1 h followed by 1 equiv of ethyl nicotinate (9)
gave an 88% yield of triketone 10 (as its enol). Cycliza-
o
tion of 10 at 150 C under reduced presure (3 mmHg) for
0.5 h gave a 79% yield of pyrone 1B. Similarly, pyrone
1C was synthesized from ethyl 3,4-dimethoxybenzoate
(11). Hence, triketone 12 was obtained in 54% yield from
the Claisen condensation of 8 and 11 under similar
reaction conditions as those of 10. However, during
workup of this reaction, if acetic acid was not added to
neutralize the excess of base before filtration of the
crystalline product 12, the lithium salt of carboxylic acid
13 was obtained which, upon acidification and methyla-
tion with diazomethane in methylene chloride and diethyl
ether, afforded a 56% yield of the methyl ester derivative
12A. Intramolecular cyclization of 12 or 12A gave an
∼83% yield of 1C. Attempted cyclization of acid 13 under
similar conditions gave only the decarboxylation product,
1-(3,4-dimethoxyphenyl)-1,3-butadione.
Unexpectedly, a remarkable asymmetric induction was
observed from a C-4 stereogenic center in the carboxal-
dehyde, such as (S)-(-)-perillaldehyde (3) in this case.
Thus, treatment of (S)-3 with pyrones 1A, 1B, and 1C
separately gave single diastereomers 14 (78% yield), 15
(65% yield), and 16 (63% yield), respectively (Scheme 3).
dienone intermediate, 7, is involved. Other catalysts,
such as L-phenylalanine, (1S)-(+)-camphorsulfonic acid,
(+)-quinidine, (S)-2-pyrrolidinemethanol, d-camphoric
acid, and acetic acid-piperidine, were also used in the
condensation reaction, but L-proline provided the highest
yield. In all cases, racemic 6A was formed. Other
pyrones, such as 1B and 1C, also underwent the con-
densation reaction. For example, coupling of aldehyde
2 with pyrones 1B and 1C separately in the presence of
0.5 equiv of L-proline in ethyl acetate at 70 °C generated
pyranobenzopyrans 6B and 6C in 73% and 62% yields,
respectively (Scheme 1).
1
On the bases of H NMR, the structures were assigned
as 5aS and 7S: the C5a proton (for example, in 14)
resonates at δ 5.15 as a doublet of doublets with J ) 11.2
and 5.2 Hz (axial-axial and axial-equatorial couplings),
indicative of an axial hydrogen (at C5a). The cis isomers
were not detected in these reactions.
Other substituted carboxaldehydes such as 4 and 5
were synthesized and subjected to the condensation
reaction. Thus, pyrone 1A condensed with carboxalde-
Scheme 2 outlines the preparation of pyrones 1B and
1C via a small modification of a procedure which reported
1B.10a Treatment of ethyl acetoacetate (8) in diethyl
ether with 2.5 equiv of lithium diisopropylamide (LDA)
(10) (a) Narasimhan, N. S.; Ammanamanchi, R. J . Org. Chem. 1983,
48, 3945-3947. (b) Huckin, S. N.; Weiler, L. Can J . Chem. 1974, 52,
1343-1351.

6890 J . Org. Chem., Vol. 62, No. 20, 1997
Hua et al.
Sch em e 3
Sch em e 4
hydes 4 and 5 separately in the presence of 0.5 equiv of
L-proline or a catalytic amount of piperidine and acetic
acid in ethyl acetate at 60-80 °C to give a 72% yield of
a mixture of 17A and 17B (in a ratio of 1.6:1; determined
1
by H NMR) and a 62% yield of a mixture of 18A and
18B (in a ratio of 3:1), respectively (Scheme 4). Although
compounds 17A and 17B were not separately isolated,
oxidation of this mixture with 1,1,1-triacetoxy-1,1-dihy-
dro-1,2-benziodoxol-3(1H)-one11 in CH2Cl2 at room tem-
perature gave the corresponding C-6 ketone 19. Reduc-
tion of this ketone with diisobutylaluminum hydride
(Dibal-H) in THF provided pure cis alcohol 17A in 87%
yield and 17B in 9% yield. Pyranobenzopyrans 18A and
18B were separated by column chromatography, and the
structure of the cis isomer 18A was unequivocally
determined by single-crystal X-ray analysis. Basic hy-
drolysis of pure 18A with K2CO3 in MeOH at room
temperature gave pure alcohol 17A (Scheme 4).
Sch em e 5
Aldehydes 4 and 5 were synthesized by a modification
of the procedure reported by Corey and Erickson12
(Scheme 5). Bromination of 2-methylcyclohexanone (20)
with 1 equiv of N-bromosuccinimide13 in refluxing CCl4
for 12 h quantitatively yielded 2-bromo-2-methylcyclo-
hexanone which underwent dehydrobromination when
treated with 3 equiv of Li2CO3 and 3 equiv of LiBr in
N,N-dimethylformamide (DMF)14 at 130 °C for 3 h to
provide a 72% yield of 2-methyl-2-cyclohexen-1-one (21).15
1,2-Addition reaction of 21 with 1.5 equiv of lithiated 1,3-
dithiane [generated from 1,3-dithiane (22) treated with
n-BuLi in THF] in THF at -10 °C gave a 96% yield of
the 1,2-adduct 23. Rearrangement of 23 with 1% sulfuric
acid in p-dioxane (58% yield) followed by removal of the
dithiane protecting group of the resulting alcohol (24)
with N-chlorosuccinimide (NCS) and silver nitrate in
acetonitrile-water gave aldehyde 4 (50% yield). Alde-
hyde 4 decomposes at room temperature in a few days.
A more stable aldehyde, 5, was synthesized in better yield
from the rearrangement reaction of 23 in formic acid-
THF in the presence of a catalytic amount of p-toluene-
sulfonic acid (70% yield) followed by removal of the
dithiane moiety with NCS-AgNO3 (59% yield) (Scheme
5). Formic acid rearrangement leads to the desired
product, 1-[2-(1,3-dithianyl)]-3-(formyloxy)-2-methyl-1-
(11) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
(12) Corey, E. J .; Erickson, B. W. J . Org. Chem. 1971, 36, 3553-
3560.
(13) Rinne, W. W.; Deutsch, H. R.; Bowman, M. I.; J offe, I. B. J .
Am. Chem. Soc. 1950, 72, 5759-5760.
(14) Stotter, P. L.; Hill, K. A. J . Org. Chem. 1973, 38, 2576-2578.
(15) Enone 21 had been synthesized from the chlorination followed
by dehydrochlorination of 20: Warnhoff, E. W.; Martin, D. G.; J ohnson,
W. S. Organic Syntheses; New York, 1963; Collect. Vol. 4, pp 162-
166.

One-Pot Condensation of Pyrones and Enals
J . Org. Chem., Vol. 62, No. 20, 1997 6891
Sch em e 6
) 1.1 µM). Interestingly, 6B is an inhibitor of L1210 cell
growth and is almost as potent as the known S phase-
specific anticancer drug cytosine â-D-arabionofuranoside,
which was used for comparison.17 In contrast, tride-
acetylpyripyropene A has no inhibitory activity under
similar bioassay conditions. The competitive inhibitions18
of various tricyclic pyrones with acetylthiocholine using
electric eel AChE and fetal bovine serum AChE were
studied. The AChE inhibition constants Ki for 6A, 18A,
27A, and 29A are 7, 5, 8, and 4 µM, respectively (Ki of
tacrine is 1 nM and was used for comparison).19
III. Con clu sion s
A high-yielding one-pot condensation of 6-substituted
4-hydroxy-2-pyrones with substituted 1-cyclohexenecar-
boxaldehydes has been developed. A 1,2-addition reac-
tion followed by dehydration and then ring closure via a
6Π electrocyclic process is proposed. Stereoselective ring-
closure reactions are observed when (S)-4-isopropenyl-
1-cyclohexenecarboxaldehyde (perillaldehyde) is used;
2-substitution (such as with methyl) of cyclohexenecar-
boxaldehydes decreases the selectivity in the electrocyclic
reaction. Application of this method in the construction
of (+)-pyripyropenes and arisugacin is being studied.
Several of the tricyclic pyrones strongly inhibit AChE
activity, DNA synthesis, and tumor cell growth in vitro.
Many biologically active tricyclic compouds, such as
analogs with nitrogen and sulfur at the 2 and 5 positions,
should be synthesized by this method, and we plan to
undertake that study in the future.
cyclohexene (25) as well as 3-[2-(1,3-dithianyl)]-2-methyl-
2-cyclohexen-1-ol (24), isolated in 9% yield.
In the condensation of formyloxy aldehyde 5 with
pyrones 1B and 1C, some of the formyloxy groups were
hydrolyzed, leading to the corresponding alcohols (Scheme
6). Hence, treatment of aldehyde 5 with pyrone 1B and
0.5 equiv of L-proline in ethyl acetate at 70 °C afforded a
39% yield of formates 26A and 26B (in a ratio of 2:1)
and an 11% yield of alcohols 27A and 27B (ratio of 2:1).
Similarly, condensation of 5 with pyrone 1C gave a 48%
yield of 28A and 28B (2:1) and a 24% yield of 29A and
29B (2:1). However, when the condensation reactions
were carried out under anhydrous conditions (adding 3
Å molecular sieves), the alcohol isomers such as 29A and
29B were not found and a 4.8:1 ratio of 28A and 28B
was obtained. These cis and trans isomers (e.g., 26A and
26B, etc.) were separated by silica gel column chroma-
tography. Condensation of alcohol 4 with pyrone 1C also
provided a mixture of the cis and trans adducts 29A and
29B (2:1). The lack of stereoselectivity in the electrocyclic
ring closure reactions of these 2-methyl-3-hydroxy- and
3-(formyloxy)cyclohexenecarboxaldehydes (4 and 5) may
be attributed to the presence of the 2-methyl substituent.
IV. Exp er im en ta l Section
Gen er a l Meth od s. Nuclear magnetic resonance spectra
were obtained at 400 MHz for 1H and 100 MHz for 13C in
deuteriochloroform, unless otherwise indicated. Infrared spec-
tra are reported in wavenumbers (cm-1). Mass spectra were
taken from a Hewlett-Packard 5890 Series II GC-HPLC-MS.
FAB spectra were taken by using Xe beam (8 KV) and
m-nitrobenzyl alcohol as matrix. 4-Hydroxy-6-methyl-2-py-
rone (1A), ethyl nicotinate (9), ethyl 3,4-dimethoxybenzoate
(11), ethyl acetoacetate (8), (S)-perillaldehyde (3), 2-methyl-
cyclohexanone (20), 1,3-dithiane (22), and L-proline were
purchased from Aldrich Chemical Co. Davisil silica gel, grade
643 (200-425 mesh), was used for the flash column chromato-
graphic separation. THF and diethyl ether were distilled over
sodium and benzophenone before used. Methylene chloride
was distilled over CaH2, and toluene and benzene were
distilled over LiAlH4. Ethyl acetate was dried over CaCl2,
filtered, and distilled under argon atmosphere.
Gen er a l P r oced u r e for th e Con d en sa tion of P yr on e
a n d En a l. The following reaction procedure is representative:
3-Met h yl-1H,7H-5a ,6,8,9-t et r a h yd r o-1-oxop yr a n o[4,3-
b][1]ben zop yr a n (6A). A solution of 0.100 g (0.91 mmol) of
cyclohexenecarboxaldehyde (2), 0.115 g (0.91 mmol) of 4-hy-
droxy-6-methyl-2-pyrone (1A), and 0.052 g (0.455 mmol) of
L-proline in 5 mL of ethyl acetate was heated at 70 °C under
an argon atmosphere for 24 h. The mixture was cooled to room
temperature, diluted with 100 mL of methylene chloride,
washed twice with 30 mL portion of a saturated aqueous
NaHCO3 solution, with 60 mL of water, and then with 60 mL
1
In the H NMR spectra, similar to that of 18A, the C6
protons of 26A, 27A, 28A, and 29A appear as a doublet
of doublets with J ) 11-12 and 4-5 Hz (axial-axial and
axial-equatorial couplings), indicative of a axial hydro-
gen (at C6).
Some biological activities of the tricyclic pyrones have
been evaluated, including their ability to inhibit acetyl-
cholinesterase (AChE) activity, DNA synthesis, and
tumor cell growth. At 50 µM, four tricyclic pyrones, 6B,
6C, 28A, and 29A, remarkably inhibit DNA synthesis
and tumor cell growth in the murine L1210 system in
vitro.16 Among these four compounds, 6C is the most
effective against DNA synthesis (IC50 ) 8.5 µM) whereas
6B is the most effective against leukemic cell growth (IC50
(17) Chabner, B. A.; Myers, C. E. In Cancer Principles and Practice
of Oncology; DeVita, V. T., Hellman, S., Rosenberg, S. A., Eds.; J . B.
Lippincott Co.: Philadelphia, 1985, pp 287-328.
(18) (a) Ralston, J . S.; Rush, R. S.; Doctor, B. P.; Wolfe, A. D. J .
Biol. Chem. 1985, 260, 4312-4318. (b) Ellman, G. L.; Courtney, K.
D.; Anders, V., J r.; Featherstone, R. M. Biochem. Pharmacol. 1961, 7,
88-95.
(16) Perchellet, J . P.; Newell, S. W.; Ladesich, J . B.; Perchellet, E.
M.; Chen, Y.; Hua, D. H. Proc. Am. Assoc. Cancer Res. 1997, 38, 610-
611.
(19) Details of the biological studies along with acyl-CoA:cholesterol
acyltransferase (ACAT) inhibitory activities of various pyrone deriva-
tives will be reported in separate manuscripts in due course.

6892 J . Org. Chem., Vol. 62, No. 20, 1997
Hua et al.
of brine, dried (MgSO4), filtered, and concentrated to give 0.200
g of crude product. Column chromatography on silica gel of
the crude product using a gradient mixture of hexane:ether
as eluant gave 0.150 g (76% yield) of 6A and 6 mg (5%
recovery) of 1A. Compound 6A: mp 110-112 oC; X-ray
analysis was carried out on a single crystal obtained from the
recrystallization from ether-hexane: IR (Nujol) ν 1710 (s,
ta n oa te (12A). To a cold (-20 °C) solution of 8.9 mL (63.7
mmol) of diisopropylamine in 100 mL of diethyl ether under
argon was added 28.1 mL (63.7 mmol; 2.27 M solution in
hexanes) of n-BuLi via syringe, and the solution was stirred
at 0 °C for 45 min. In a separate flask, 3.32 g (25.5 mmol) of
freshly distilled ethyl acetoacetate (8) and 50 mL of diethyl
ether were added and the solution was cooled to -78 °C. To
this solution was added the LDA solution (above) via cannula
followed by addition of 3.84 mL (25.5 mmol) of N,N,N′,N′-
tetramethylethylenediamine (TMEDA) (distilled from LiAlH4)
via syringe, and the solution was stirred at 0 °C for 3 h. To
this dianion solution was added a solution of 5.0 g (25.5 mmol)
of methyl 3,4-dimethoxybenzoate (11) in 50 mL of diethyl ether
via cannula, and the reaction solution was warmed to room
temperature and stirred for 40 h. Acetic acid (4 mL) was
added, and the mixture was stirred for 10 min. The reaction
mixture was filtered through a fritted funnel, washed with 70
mL of ether, and the solid (desired product) was set aside. The
organic filtrate from the above filtration was washed with 100
mL of 0.5 N HCl and then with 80 mL of brine, dried (MgSO4),
and concentrated to give ethyl ester 12 and starting material
11. The solid that was set aside was then dissolved in 100
mL of 1 N HCl and extracted three times with a 50 mL portion
of methylene chloride. The combined methylene chloride
extracts were washed with 80 mL of brine, dried (MgSO4), and
concentrated to give additional product 12. The combined
crude products were column chromatographed on silica gel
using a gradient mixture of hexane and ethyl acetate as eluant
to give 4.053 g (54% yield) of pure 12 and 1.370 g (28%
recovery) of 11. 12: 1H NMR δ 7.51 (dd, J ) 8.5 Hz, 2 Hz, 1
H, C5′ H, Ar), 7.44 (d, J ) 2 Hz, 1 H, C2′ H), 6.89 (d, J ) 8.5
Hz, 1 H, C6′ H), 6.25 (s, 1 H, dCH of enol at C4 and 5), 4.22
(q, J ) 7 Hz, 2 H, OCH2), 3.93 (s, 6 H, 2 OMe), 3.45 (s, 2 H,
CH2), 1.30 (t, J ) 7 Hz, 3 H, Me); 13C NMR δ 186.3 (s, C3),
184.1 (s, C5), 167.8 (s, C1), 153.1 (s, C4′ Ar), 149.1 (s, C3′),
127.1 (s, C1′), 121.5 (d, C2′), 110.5 (d, C5′), 109.6 (d, C6′), 96.1
(d, C4), 61.5 (t, OCH2), 56.1 (q, OMe), 56.0 (q, OMe), 45.2 (t,
CH2), 14.2 (q, Me); MS FAB, m/ z 295 (M + 1), 294 (M+).
If acetic acid was not added before the reaction mixture was
filtered in the workup procedure, 5-(3,4-dimethoxyphenyl)-3,5-
dioxopentanoic acid (13) was produced. Similar aqueous
treatment, followed by methylation of the combined carboxylic
acid products (dissolved in 50 mL of CH2Cl2) with a solution
of diazomethane in diethyl ether, concentration on rotary
evaporator, and then column chromatographic separation on
silica gel using a gradient mixture of hexane and ethyl acetate
as eluant gave 3.798 g (56% yield) of pure methyl ester 12A:
1H NMR δ 7.51 (dd, J ) 8.5 Hz, 2 Hz, 1 H, C5′ H, Ar), 7.45 (d,
J ) 2 Hz, 1 H, C2′ H), 6.9 (d, J ) 8.5 Hz, 1 H, C6′ H), 6.24 (s,
1 H, dCH of enol at C4 and 5), 3.95 (s, 6 H, 2 OMe on Ar
ring), 3.77 (s, 3 H, MeO), 3.47 (s, 2 H, CH2); 13C NMR δ 186.2
(s, C3 CdO), 184.1 (s, C5 dC-O), 168.2 (s, CdO ester), 153.2
(s, C4′), 149.1 (s, C3′), 127.0 (s, C1′), 121.5 (d, C2′), 110.6 (d,
C5′), 109.7 (d, C6′), 96.2 (d, C4), 56.1 (q, OMe), 56.0 (q, OMe),
52.3 (q, OMe of ester), 44.9 (t, CH2); MS FAB, m/ z 281 (M +
1), 280 (M+).
1
CdO), 1630 (CdC), 1560. H NMR δ 6.07 (s, 1 H, C10H), 5.7
(s, 1 H, C4H), 5.02 (dd, J ) 11, 5 Hz, 1 H, C5aH), 2.41 (m, 1
H, C9H), 2.18 (s, 3 H, Me), 2.13 (m, 1 H), 2.02-1.88 (m, 2 H),
1.8-1.7 (m, 2 H), 1.5-1.4 (m, 2 H); 13C NMR δ 174.0 (s, CdO),
163.2 (s, C3), 161.4 (s, C4a), 133.1 (s, C10a), 109.2 (d, C10),
99.8 (d, C4), 97.3 (s, C9a), 79.7 (s, C5a), 35.2 (t), 33.1 (t), 26.9
(t), 24.5 (t), 20.1 (q, Me); MS (CI) m/ z 219 (M + 1). Anal. Calcd
for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.39; H, 6.53.
Eth yl 5-(3-P yr id yl)-3,5-d ioxop en ta n oa te (10). To a cold
(-10 °C) solution of 13.45 mL (96.2 mmol) of diisopropylamine
in 150 mL of diethyl ether under argon was added 42.36 mL
(96.2 mmol; 2.27 M solution in hexanes) of n-BuLi via syringe,
and the solution was stirred for 1 h. In a separate flask, 5 g
(38.5 mmol) of freshly distilled ethyl acetoacetate (8) and 60
mL of diethyl ether were added and the solution was cooled
to -78 °C. To this solution was added the LDA solution
(above) via cannula followed by 5.8 mL (38.5 mmol) of
N,N,N′,N′-tetramethylethylenediamine (TMEDA) (distilled
from LiAlH4) via syringe, and the solution was stirred at 0 °C
for 3 h. To this dianion solution was added a solution of 5.81
g (38.5 mmol) of ethyl nicotinate (9; freshly distilled) in 60 mL
of diethyl ether via cannula, and the reaction solution was
warmed to room temperature and stirred for 30 h. After 5.5
mL of acetic acid was added and the solution was stirred for
10 min, it was filtered through a fritted funnel and the solid
(desired product; exists as a protonated salt) was washed with
200 mL of diethyl ether. The filtrate was concentrated to give
1.691 g of material, and the NMR spectrum indicated that it
is a mixture of starting material and some unidentified
components. The solid was dissolved in 160 mL of distilled
water, to it, 60 mL of 1 N HCl was added, and the solution
was extracted three times with a 120 mL portion of methylene
chloride. The combined extracts were washed with 100 mL
of brine, dried (MgSO4), and concentrated to give 7.921 g (88%
yield) of the desired product 10. The 1H NMR spectrum of
this material indicated it was sufficiently pure and to be used
in the next reaction without purification: mp 38.5-39 °C; 1H
NMR δ 9.07 (s, 1 H, C-2′ H, pyr), 8.74 (d, J ) 4.6 Hz, 1 H, C6′
H, pyr), 8.16 (d, J ) 8 Hz, C4′ H), 7.41 (dd, J ) 8 Hz, 4.6 Hz,
C5′ H), 6.32 (s, 1 H, dCH of enol; the compound exists
completely in its C4 enolic form), 4.22 (q, J ) 7.2 Hz, 2 H,
OCH2), 3.5 (s, 2 H, CH2), 1.3 (t, J ) 7.2 Hz, 3 H, Me); 13C NMR
δ 189.9 (s, CdO, C3), 180.0 (s, O-Cd, C5), 167.1 (s, CdO
ester), 152.7 (d, C2′), 148.1 (d, C6′), 134.3 (d, C4′), 129.7 (s,
C3′), 123.4 (d, C5′), 97.2 (d, dCH, C4), 61.4 (t, OCH2), 45.7 (t,
CH2), 13.9 (q, Me); MS FAB, m/ z 236 (M + 1), 235 (M+).
4-H yd r oxy-6-(3-p yr id yl)-2-p yr on e (1B). To a flask
equipped with an adaptor connected to a manifold and
maintained under argon was added 0.594 g (2.53 mmol) of
ester 10. The flask was then connected to a vacuum set at 3
mmHg pressure and heated over an oil bath at 150 °C. It was
kept at this temperature for 0.5 h, and then cooled to room
temperature. Diethyl ether was added to the reaction mixture
which was then filtered and the solid residue was washed with
diethyl ether. The solid was dried in vacuo; 0.380 g (79% yield)
of 1B. The filtrate was concentrated and column chromato-
graphed to give 0.065 g (10.9% recovery) of starting ester 10.
Compound 1B: recrystallization from p-dioxane-hexane (1:
1) gave yellow solids; mp 205-207 °C dec; lit.10a mp 207-209
°C; 1H NMR (CDCl3 and DMSO-d6) δ 9.03 (s, 1 H, C2′ H), 8.67
(d, J ) 5.2 Hz, 1 H, C6′ H, pyr ring), 8.13 (d, J ) 8 Hz, 1 H,
C4′ H), 7.41 (dd, J ) 8 Hz, 5.2 Hz, 1 H, C5′ H), 6.56 (d, J ) 1.6
Hz, 1 H, C5 H), 5.62 (d, J ) 1.6 Hz, 1 H, C3 H); 13C NMR
(DMSO-d6) δ 170.3 (s, C2), 162.7 (s, C4), 157.9 (s, C6), 151.3
(d, C2′), 146.6 (d, C6′), 133.0 (d, C4′), 127.1 (s, C1′), 123.9 (d,
C5′), 99.6 (d, C3), 90.2 (d, C5); MS FAB, m/ z 190 (M + 1), 189
(M+).
4-Hyd r oxy-6-(3,4-d im eth oxyp h en yl)-2-p yr on e (1C). A
flask containing the methyl ester 12A (1.56 g; 5.57 mmol) was
connected into a vacuum system to provide ∼3 mmHg pressure
and heated in an oil bath to 160 °C over a 1 hour period. The
reaction was kept at this temperature for another hour, cooled
to room temperature, diluted with a small amount of ether,
and filtered to collect the yellow solids, which were washed
with ether and dried under vacuum to give 0.56 g of pyrone
1C. The filtrate was concentrated to give 0.921 g of starting
ester 12A. This starting material was subjected to the same
procedure as described above to give a total of 1.144 g (83%
yield) of pyrone 1C. Compound 1C: mp 210-212 °C; 1H NMR
δ 7.40 (dd, J ) 8.3 Hz, 2 Hz, 1 H, C6′ of the phenyl ring), 7.33
(d, J ) 2 Hz, 1 H, C2′ of Ph ring), 6.91 (d, J ) 8.3 Hz, 1 H,
C5′), 6.40 (s, C5 H), 5.55 (s, 1 H, C3 H), 3.95 (s, 3 H, OMe),
3.94 (s, 3 H, OMe); 13C NMR (DMSO-d6) δ 170.7 (s, C2), 163.1
(s, C4), 160.3 (s, C6), 151.2 (s, C4′), 148.9 (s, C3′), 123.5 (s,
C1′), 118.8 (d, C3), 111.7 (d, C2′), 108.5 (d, C5′), 97.0 (d, C6′),
88.7 (d, C5), 55.7 (q, OMe), 55.6 (q, OMe); MS FAB, m/ z 249
E t h yl 5-(3,4-Dim et h oxyp h en yl)-3,5-d ioxop en t a n oa t e
(12) a n d Meth yl 5-(3,4-Dim eth oxyp h en yl)-3,5-d ioxop en -

One-Pot Condensation of Pyrones and Enals
J . Org. Chem., Vol. 62, No. 20, 1997 6893
(M + 1), 248 (M+). Under similar reaction conditions, ethyl
ester 12 provided a similar yield (84% yield) of the ring closure
product 1C.
1H ,7H -5a ,6,8,9-t e t r a h y d r o -1-o x o p y r a n o [4,3-b ][1]-
ben zop yr a n (16). From 0.200 g (0.81 mmol) of 1B and 0.121
g (0.81 mmol) of aldehyde (S)-3, 0.193 g (63% yield) of 16 was
obtained after column chromatographic separation: yellow
3-(3-P yr idyl)-1H,7H-5a,6,8,9-tetr ah ydr o-1-oxopyr an o[4,3-
b][1]ben zop yr a n (6B). From 0.344 g (1.82 mmol) of pyrone
1B and 0.2 g (1.82 mmol) of aldehyde 2, 0.373 g (73% yield) of
6B was obtained after column chromatographic separation: IR
(Nujol) ν 3070, 1690, 1620, 1540, 1200, 1060, 1020; 1H NMR δ
8.99 (d, J ) 2 Hz, 1 H, C2′ H, pyr), 8.65 (dd, J ) 4.9 Hz, 2 Hz,
1 H, C6′H), 8.1 (dt, J ) 8 Hz, 2 Hz, 1 H, C4′H), 7.38 (dd, J )
8 Hz, 4.9 Hz, 1 H, C5′H), 6.44 (s, 1 H, C10 H), 6.14 (s, 1 H, C4
H), 5.14 (dd, J ) 11 Hz, 5 Hz, 1 H, C5a H), 2.47 (m, 1 H, C9
H), 2.19 (m, 1 H, C9 H), 2.03 (m, 1 H), 1.94 (m, 1 H), 1.86-
1.76 (m, 2 H), 1.5 (dt, J ) 13 Hz, 3.4 Hz, 1 H), 1.37 (dt, J ) 13
Hz, 3.4 Hz, 1 H); 13C NMR δ 162.6 (s, C1), 161.4 (s, C4a), 156.5
(s, C3), 151.2 (d, C2′), 146.7 (d, C6′), 134.9 (s, C1′), 132.8 (d,
C4′), 127.6 (s, C10a), 123.7 (d, C5′), 109.2 (d, C10), 99.8 (s,
C9a), 98.6 (d, C4), 80.1 (d, C5a), 35.3 (t), 33.4 (t), 27.0 (t), 24.6
(t); MS FAB, m/ z 282 (M + 1, 100%), 281 (M+), 252, 202, 148,
136, 106. Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37.
Found: C, 72.33; H, 5.42.
3-(3,4-Dim eth oxyp h en yl)-1H,7H-5a ,6,8,9-tetr a h yd r o-1-
oxop yr a n o[4,3-b][1] ben zop yr a n (6C). From 0.200 g (0.81
mmol) of 1C and 0.135 g (0.81 mmol) of aldehyde 2, 0.200 g
(62% yield) of 6C was obtained after column chromatographic
separation: mp 137-138 °C; IR (Nujol) ν 3010, 3050, 1700,
1650, 1630, 1560, 1520, 1280, 1240, 1150; 1H NMR δ 7.37 (dd,
J ) 8.5 Hz, 2 Hz, 1 H, C6′ H, Ph ring), 7.28 (d, J ) 2 Hz, 1 H,
C2′ H), 6.9 (d, J ) 8.5 Hz, 1 H, C5′ H), 6.29 (s, 1 H, C10 H),
6.14 (s, 1 H, C4 H), 5.07 (dd, J ) 11.4 Hz, 5.2 Hz, 1 H, C5a H),
3.94 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 2.45 (d, J ) 14 Hz, 1 H,
C9 H), 2.18 (m, 1 H), 2.02 (m, 1 H), 1.92 (m, 1 H), 1.78 (m, 2
H), 1.54-1.34 (m, 2 H); 13C NMR δ 163.4 (s, C1), 162.0 (s, C4a),
159.3 (s, C3), 151.3 (s, C4′), 149.2 (s, C3′), 133.6 (s, C1′), 124.1
(s, C10a), 118.9 (d, C2′), 111.1 (d, C5′), 109.4 (d, C10), 108.1
(d, C6′), 98.1 (s, C9a), 96.1 (d, C4), 79.8 (d, C5a), 56.1 (q, OMe),
56.0 (q, OMe), 35.3 (t), 33.3 (t), 27.0 (t), 24.6 (t); MS FAB, m/ z
341 (M + 1, 100%), 340 (M+), 307, 289, 261, 235, 219. Anal.
Calcd for C20H20O5: C, 70.58; H, 5.92. Found: C, 70.31; H,
6.11.
(5aS,7S)-7-Isopr open yl-3-m eth yl-1H,7H-5a,6,8,9-tetr ah y-
d r o-1-oxop yr a n o[4,3-b][1] ben zop yr a n (14). From 1.000
g (7.93 mmol) of 1A and 1.191 g (7.93 mmol) of aldehyde (S)-
3, 1.596 g (78% yield) of 14 was obtained after column
chromatographic separation: yellow solids, mp 140-141 °C;
[R]22D ) +31.9° (c 0.75, CHCl3); 1H NMR δ 6.1 (s, 1 H, C10 H),
5.72 (s, 1 H, C4 H), 5.1 (dd, J ) 11 Hz, 5 Hz, 1 H, C5a H), 4.75
(m, 1 H, dCH), 4.73 (m, 1 H, dCH), 2.48 (ddd, J ) 14 Hz, 4
Hz, 2.4 Hz, 1 H), 2.22-2.02 (series of m, 3 H), 2.19 (s, 3 H,
C4-Me), 1.88-1.72 (series of m, 2 H), 1.74 (s, 3 H, MeCd), 1.31
(ddd, J ) 25 Hz, 12.8 Hz, 4 Hz, 1 H); 13C NMR δ 163.4 (s,
CdO), 162.6 (s, C3), 161.7 (s, C4a), 147.9 (s, C10a), 132.3 (s,
dC), 109.8 (d, C10), 109.6 (t, dCH2), 99.9 (d, C4), 97.5 (s, C9a),
79.4 (s, C5a), 43.6 (d, C7), 40.0 (t), 32.5 (t), 32.1 (t), 20.9 (q,
Me), 20.3 (q, Me); MS FAB, m/ z 259 (M+1; 70%), 258, 257,
215, 189, 139 (100%). Anal. Calcd for C16H18O3: C, 74.40; H,
7.02. Found: C, 74.17; H, 7.33.
solids, mp 119-120 °C; [R]22 ) +90.4° (c 0.76, CHCl3); 1H
D
NMR δ 7.37 (dd, J ) 8.8 Hz, 2.4 Hz, 1 H, C6′ H, Ph ring), 7.28
(d, J ) 2.4 Hz, 1 H, C2′ H), 6.89 (d, J ) 8.8 Hz, 1 H, C5′ H),
6.29 (s, 1 H, C10 H), 6.17 (s, 1 H, C4 H), 5.15 (dd, J ) 11 Hz,
5 Hz, 1 H, C5a H), 4.75 (m, 2 H, dCH2), 3.94 (s, 3 H, OMe),
3.92 (s, 3 H, OMe), 2.52 (ddd, J ) 13 Hz, 6 Hz, 3.6 Hz, 1 H),
2.26-2.24 (a series of m, 3 H), 1.88-1.76 (m, 2 H), 1.75 (s, 3
H, Me), 1.34 (m, 1 H); 13C NMR δ 163.6 (s, C1), 162.1 (s, C4a),
159.7 (s, C3), 151.6 (s, C4′), 149.4 (s, C3′), 148.0 (s, dC), 132.8
(s, C1′), 124.3 (s, C10a), 119.1 (d, C2′), 111.3 (d, C5′), 109.9 (d,
dCH2), 109.9 (d, C10), 108.4 (d, C6′), 98.3 (s, C9a), 96.2 (d,
C4), 79.5 (d, C5a), 56.3 (q, OMe), 56.2 (q, OMe), 43.6 (d, C7),
40.1 (t), 32.6 (t), 32.1 (t), 20.9 (q, Me); MS FAB, m/ z 381 (M+1,
100%), 380 (M+). Anal. Calcd for C23H24O5: C, 72.61; H, 6.36.
Found: C, 72.43; H, 6.17.
P r ep a r a tion of 2-Meth yl-2-cycloh exen -1-on e (21).
A
solution of 15.00 g (0.134 mol) of 2-methyl-1-cyclohexanone (20)
and 23.84 g (0.134 mol) of N-bromosuccinimide in 150 mL of
carbon tetrachloride was stirred and heated to reflux for 12 h
under argon. The mixture was cooled to room temperature
and filtered through Celite to remove succinimide, and the
filter cake was washed with 150 mL of ether. The filtrate was
concentrated to give 25.60
g (100% yield) of 2-bromo-
2-methyl-1-cyclohexanone: 1H NMR δ 3.21 (td, J ) 16 Hz, 8
Hz, 1 H, CH-CO), 2.36 (m, 2 H), 2.06 (m, 2 H), 1.82 (s, 3 H,
Me), 1.77 (m, 2 H), 1.62 (m, 1 H). This material was used in
the following step without further purification.
A mixture of 25.60 g (0.134 mol) of 2-bromo-2-methylcyclo-
hexanone (above), 29.70 g (0.4 mol) of Li2CO3, and 34.90 g (0.4
mol) of LiBr in 300 mL of DMF was heated at 130 °C under
argon for 3 h. The reaction mixture was cooled to room
temperature, diluted with 400 mL of water, and extracted
three times with ether (300 mL × 2 and 200 mL). The
combined extract was dried (MgSO4) and concentrated on a
rotary evaporator to give 12.96 g of crude product which was
vacuum distilled to give 10.6 g (72% yield) of 21, bp 90-95
°C/45 mmHg; lit.13 93-97 °C/25 mmHg; 1H NMR δ 6.75 (broad
s, 1 H, dCH), 2.42 (dd, J ) 5.6 Hz, 5 Hz, 2 H), 2.33 (m, 2 H),
1.95 (pent, J ) 8 Hz, 2 H), 1.78 (q, J ) 2 Hz, 3 H, Me); 13C
NMR δ 199.9 (s, CdO), 145.6 (d, dCH), 135.7 (s, dC), 38.3 (t),
26.0 (t), 23.3 (t), 16.0 (q).
1-[2-(1,3-Dith ia n yl)]-2-m eth yl-2-cycloh exen -1-ol (23).
To a cold (-10 °C) solution of 6.71 g (55.9 mmol) of 1,3-dithiane
(22) in 50 mL of THF under argon was added 24.6 mL (55.9
mmol; from a 2.27 M solution in hexane) of n-BuLi dropwise
via syringe over 35 min, and the resulting solution was stirred
for 2 h. In a separate flask, a solution of 4.10 g (37.7 mmol)
of 21 in 25 mL of THF was prepared and added via cannula
into the above dithiane anion solution. The solution was
stirred at -10 °C for 1 h and kept in the refrigerator for 18 h,
diluted with 100 mL of water, stirred for 10 min, and extracted
three times with diethyl ether (100, 75, and 50 mL). The
combined extracts were washed twice with 100 mL portion of
brine, dried (MgSO4), filtered, and concentrated to give 13.15
g of crude product. Column chromatographic separation on
silica gel using a gradient mixture of hexane:ether as eluant
gave 8.21 g (96% yield) of 23 as an oil: 1H NMR δ 5.74 (t, J )
4 Hz, 1 H, dCH), 4.42 (s, 1 H, CH-S), 3.0-2.8 (m, 4 H, CH2S),
2.28 (s, 1 H, OH), 2.16-1.6 (series of m, 8 H), 1.82 (broad s, 3
H, Me); 13C NMR δ 133.8 (s, dC), 130.3 (d, dCH), 74.0 (s, CO),
59.1 (d, CH-S), 33.9 (t, CH2S), 31.8 (t, CH2S), 31.3 (t, CH2),
26.4 (t, CH2), 25.6 (t, CH2), 18.7 (t, CH2), 17.8 (q, Me); MS (EI)
m/ z 230 (M+).
(5a S,7S)-7-Isop r op en yl-3-(3-p yr id yl)-1H ,7H -5a ,6,8,9-
tetr a h yd r o-1-oxop yr a n o[4,3-b][1]ben zop yr a n (15). From
0.200 g (1.06 mmol) of 1B and 0.160 g (1.06 mmol) of aldehyde
(S)-3, 0.221 g (65% yield) of 15 was obtained after column
chromatographic separation; yellow solids, mp 99-100 °C;
[R]22 ) +100.6° (c 0.77, CH2Cl2); 1H NMR δ 8.98 (d, J ) 2
D
Hz, 1 H, C2′ H, pyr), 8.65 (dd, J ) 4.8 Hz, 2 Hz, 1 H, C6′H),
8.07 (dt, J ) 8 Hz, 2 Hz, 1 H, C4′H), 7.38 (dd, J ) 8 Hz, 4.8
Hz, 1 H, C5′H), 6.44 (s, 1 H, C10 H), 6.15 (s, 1 H, C4 H), 5.17
(dd, J ) 11.6 Hz, 5.2 Hz, 1 H, C5a H), 4.74 (m, 2 H, dCH2),
2.52 (m, 1 H), 2.26-1.75 (a series of m, 5 H), 1.75 (s, 3 H, Me),
1.3 (m, 1 H); 13C NMR δ 162.5 (s, C1), 161.3 (s, C4a), 156.6 (s,
C3), 151.2 (d, C2′), 147.6 (d, C6′), 146.7 (s, C)), 133.9 (s, C3′),
132.7 (d, C4′), 127.4 (s, C10a), 123.7 (d, C5′), 109.9 (d, C10),
109.4 (t, dCH2), 99.8 (s, C9a), 98.4 (d, C4), 79.6 (d, C5a), 43.4
(d, C7), 39.9 (t), 32.5 (t), 31.9 (t), 20.8 (q, Me); MS FAB, m/ z
322 (M+1, 100%), 278 (M+), 252, 202, 148, 106. Anal. Calcd
for C20H19NO3: C, 74.75; H, 5.96. Found: C, 74.48; H, 6.12.
(5a S ,7S )-7-I s o p r o p e n y l-3-(3,4-d im e t h o x y p h e n y l)-
3-[2-(1,3-Dith ia n yl)]-2-m eth yl-2-cycloh exen -1-ol (24). A
solution of 1.031 g (4.48 mmol) of alcohol 23 in 50 mL of
p-dioxane and 75 mL of 1% aqueous solution of H2SO4 was
stirred at 25 °C for 5.5 h and extracted three times with a 100
mL portion of diethyl ether. The combined extracts were
washed with 80 mL of saturated aqueous NaHCO3, twice with
80 mL portions of water, and 80 mL of brine, dried (MgSO4),
concentrated, and column chromatographed on silica gel using
a gradient mixture of hexane and diethyl ether as eluant to

6894 J . Org. Chem., Vol. 62, No. 20, 1997
Hua et al.
give 0.533 g (58% yield based on recovered starting material
23) of 24 as an oil and 0.110 g (11% recovery) of 23. Compound
24: 1H NMR δ 5.09 (s, 1 H, CHS), 3.97 (broad s, 1 H, CHO),
3.04-2.95 (m, 2 H, CH2S), 2.87-2.81 (m, 2 H, CH2S), 2.32-
2.24 (m, 1 H), 2.16-2.07 (m, 2 H), 1.91 (t, J ) 4 Hz, 3 H, Me),
1.89-1.58 (a series of m, 5 H); 13C NMR δ 132.9 (s, C)), 131.9
(s, dC), 69.6 (d, CO), 51.1 (d, CHS), 31.8 (t), 31.4 (2 C, t, CH2S),
26.6 (t), 25.5 (t), 18.5 (t), 16.4 (q, Me); MS (EI) m/ z 230 (M+).
Anal. Calcd for C11H18OS2: C, 57.35; H, 7.87. Found: C,
57.56; H, 8.10.
17.9 (t), 14.8 (q, Me); MS FAB m/ z 169 (M + 1), 168 (M+).
Anal. Calcd for C9H12O3: C, 64.27; H, 7.19. Found: C, 63.98;
H, 7.31.
Gen er a l P r oced u r e for th e Con d en sa tion of P yr on es
w ith Ald eh yd es 4 a n d 5. cis- a n d tr a n s-3,5a -Dim eth yl-
6-(for m yloxy)-1H,7H-5a,6,8,9-tetr ah ydr o-1-oxopyr an o[4,3-
b][1]ben zop yr a n (18A a n d 18B). A solution of 0.1470 g
(0.88 mmol) of aldehyde 5, 0.11 g (0.88 mmol) of pyrone 1A,
and 0.05 g (0.4 mmol) of L-proline in 10 mL of ethyl acetate
was stirred under argon at 25 °C for 1 day, 40 °C (bath
temperature) for 3 days, and 60 °C for 1 day. The mixture
was diluted with 120 mL of methylene chloride, washed with
50 mL of saturated aqueous NaHCO3 and then with 50 mL of
brine, dried (MgSO4), concentrated, and column chromato-
graphed on silica gel using a gradient mixture of hexane and
diethyl ether as eluant to give 0.1133 g (46.5% yield) of 18A
and 0.0378 g (15.5% yield) of 18B. Compound 18A: mp 138-
3-H y d r o x y -2-m e t h y l-1-c y c lo h e x e n e -1-c a r b o x a ld e -
h yd e (4). To 0.197 g (1.16 mmol) of AgNO3 and 0.139 g (1.04
mmol) of N-chlorosuccinimide (NCS) under argon were added
6 mL of CH3CN and 2.5 mL of H2O. The solution was stirred
and cooled in an ice-water bath, and a solution of 0.059 g (0.26
mmol) of 24 in 5 mL of acetonitrile was added dropwise via
cannula. The solution was stirred at 0 °C for 45 min, and 1
mL each of saturated aqueous Na2SO3 and Na2CO3 were added
at 1-min intervals followed by 20 mL of a 1:1 mixture of
CH2Cl2-petroleum ether was also added. The resulting
mixture was filtered through Celite and the solid carefully
washed with 120 mL of 1:1 mixture of CH2Cl2 and petroleum
ether. The filtrate was transferred into a separatory funnel,
and the water layer was removed. The organic layer was
washed with 10 mL of saturated aqueous NaHCO3, dried
(MgSO4), and concentrated to give 32 mg of the crude aldehyde
4. This material can be used directly in the next reaction
without further purification. For characterization, the mixture
was separated by silica gel column chromatography and
provided 18 mg (50% yield) of pure 4. Aldehyde 4 is unstable;
elemental analysis was not performed. 4: 1H NMR δ 10.18
(s, 1 H, CHO), 4.16 (broad s, 1 H, CH-O), 2.27 (s, 3 H, Me),
2.31-1.6 (a series of m, 6 H); 13C NMR δ 192.4 (s, CdO), 154.2
(s, C)), 135.0 (s, C)), 70.3 (d, C-O), 31.8 (t), 22.7 (t), 17.9 (t),
14.9 (q, Me); MS FAB m/ z 141 (M+1, 100%), 140 (M+).
3-(F or m yloxy)-2-m eth yl-1-cycloh exen e-1-ca r boxa ld e-
h yd e (5). A solution of 0.494 g (2.15 mmol) of alcohol 23 and
three crystals of p-toluenesulfonic acid (anhydrous) in 2.43 mL
of formic acid and 15 mL of THF was stirred under argon at
25 °C for 16 h. The solution was diluted with 100 mL of diethyl
ether, washed with 40 mL of saturated aqueous NaHCO3 and
50 mL of brine, dried (MgSO4), concentrated, and column
chromatographed on silica gel using a gradient mixture of
hexane and diethyl ether as eluant to give 0.388 g (70% yield)
of 1-[2-(1,3-dithanyl)]-3-(formyloxy)-2-methyl-1-cyclohexene (25)
and 0.048 g (9% yield) of alcohol 24. Compound 25: 1H NMR
δ 8.12 (s, 1 H, CHO), 5.36 (broad s, 1 H, CH-O), 5.1 (s, 1 H,
CHS), 3.05-2.95 (m, 2 H, CH2S), 2.9-2.8 (m, 2 H, CH2S), 2.4-
2.3 (m, 1 H), 2.2-2.05 (m, 2 H), 1.94-1.6 (m, 5 H), 1.78 (s, 3
H, Me); 13C NMR δ 161.0 (s, CdO), 135.2 (s, C)), 128.4 (s,
C)), 71.7 (d, C-O), 51.0 (d, CS), 31.3 (t, 2 C, CS), 28.7 (t),
26.4 (t), 25.4 (t), 18.6 (t), 16.3 (q, Me); MS FAB m/ z 259 (M +
1), 258 (M+).
1
140 °C; IR (Nujol) ν 2980, 1720, 1690, 1630, 1550, 1110; H
NMR δ 8.14 (d, J ) 1 Hz, 1 H, CHO), 6.18 (d, J ) 2.2 Hz, 1 H,
C10 H), 5.73 (s, 1 H, C4 H), 5.31 (dd, J ) 11.6 Hz, 4.4 Hz, 1 H,
C6 H, axial H), 2.39-2.33 (m, 1 H), 2.29-2.23 (m, 1 H), 2.19
(d, J ) 0.44 Hz, 3 H, Me), 2.12-2.05 (m, 1 H), 1.88-1.8 (m, 1
H), 1.7-1.5 (m, 2 H), 1.54 (s, 3 H, Me); 13C NMR δ 162.4 (s,
CdO), 162.3 (s), 160.4 (s, 2 C), 132.7 (s, C10a), 112.5 (d, C10),
100.1 (d, C4), 97.7 (s, C9a), 84.4 (s, C5a), 76.5 (d, C6), 31.3 (t),
29.3 (t), 23.1 (t), 20.3 (q, Me), 18.9 (q, Me); MS FAB, m/ z 277
(M + 1, 100%), 230, 139, 91. Anal. Calcd for C15H16O5: C,
65.21; H, 5.84. Found: C, 65.47; H, 5.61. Single crystals were
obtained from the recrystallization in ether, and the structure
was unequivocally determined by an X-ray analysis.
Com p ou n d 18B: 1H NMR δ 8.11 (d, J ) 0.92 Hz, 1 H,
CHO), 6.23 (d, J ) 1.6 Hz, 1 H, C10 H), 5.72 (s, 1 H, C4 H),
2.44-2.28 (m, 2 H), 2.19 (d, J ) 0.6 Hz, 3 H, Me), 2.1-2.0 (m,
1 H), 1.9-1.64 (a series of m, 3 H), 1.57 (s, 3 H, Me); 13C NMR
δ 162.5 (s, CdO), 161.9 (s), 160.1 (s, 2 C), 131.6 (s, C10a), 112.2
(d, C10), 99.7 (d, C4), 97.1 (s, C9a), 82.9 (s, C5a), 74.3 (d, C6),
31.0 (t), 27.9 (t), 23.7 (t), 20.6 (q, Me), 20.1 (q, Me); MS FAB,
m/ z 277 (M + 1, 100%). Basic hydrolysis of 18B with K2CO3
in MeOH gave the corresponding C6 alcohol having exactly
the same NMR as the trans-alcohol obtained from the con-
densation of pyrone 1A and aldehyde 4.
cis- a n d tr a n s-3,5a -Dim eth yl-6-h yd r oxy-1H,7H-5a ,6,8,9-
tetr a h yd r o-1-oxop yr a n o[4,3-b][1]ben zop yr a n (17A a n d
17B). From 24.0 mg (0.188 mmol) of aldehyde 4 and 23.7 mg
(0.188 mmol) of pyrone 1A, heating with 3 mL of ethyl acetate
and 3 drops (∼15 mg) of piperidine and 3 drops of acetic acid
at 80 °C for 18 h, 33.0 mg (72% yield) of a mixture of 17A and
17B in a ratio of 1.6:1 (determined from 1H NMR spectrum)
was obtained. Compound 17A: 1H NMR δ 6.13 (d, J ) 2 Hz,
1 H, C10 H), 5.77 (s, 1 H, C4 H), 4.07 (dd, J ) 8.4 Hz, 3.4 Hz,
1 H, C6 H), 2.36-2.16 (a series of m, 2 H), 2.21 (s, 3 H, C3
Me), 2.14 (broad s, 1 H, OH), 1.98-2.04 (m, 1 H), 1.83-1.76
(m, 1 H), 1.56-1.42 (m, 2 H), 1.47 (s, 3 H, C5a Me); 13C NMR
δ 162.4 (s, C1), 162.1 (s, C4a), 158 (s, C3), 134.2 (s, C10a),
111.7 (d, C10), 100.1 (d, C4), 98.1 (s, C9a), 87.1 (s, C5a), 76.2
(d, C6), 31.6 (t), 30.9 (t), 23.2 (t), 20.4 (q, Me), 17.5 (q, Me);
MS FAB, m/ z 249 (M + 1), 248 (M+). Anal. Calcd for
C14H16O4: C, 67.73; H, 6.50. Found: C, 67.67; H, 6.72.
Com p ou n d 17B: 1H NMR δ 6.23 (d, J ) 3 Hz, 1 H, C10
H), 5.80 (s, 1 H, C4 H), 3.87 (t, J ) 1 Hz, 1 H, C6 H), 2.21 (s,
3 H, C3 Me), 1.44 (s, 3 H, C5a Me), 2.4-1.5 (a series of m, 6
H); 13C NMR δ 162.1 (s, C1), 161.7 (s, C4a), 156.2 (s, C3), 133.4
(s, C10a), 112.5 (d, C10), 99.9 (d, C4), 98.5 (s, C9a), 85.6 (s,
C5a), 73.0 (d, C6), 31.1 (t), 29.0 (t), 22.5 (t), 20.1 (q, Me), 19.5
(q, Me); MS FAB, m/ z 249 (M + 1), 248 (M+). Anal. Calcd
for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.49; H, 6.57.
cis- a n d tr a n s-3-(3-P yr id yl)-5a -m eth yl-6-(for m yloxy)-
1H,7H-5a,6,8,9-tetr ah ydr o-1-oxopyr an o[4,3-b][1]-ben zopy-
r a n (26A a n d 26B) a n d cis- a n d tr a n s-3-(3-P yr id yl)-5a -
m e t h y l-6-h y d r o x y -1H ,7H -5a ,6,8,9-t e t r a h y d r o -1-o x o -
p yr a n o[4,3-b][1]ben zop yr a n (27A a n d 27B). After con-
densation of 73 mg (0.39 mmol) of pyrone 1B and 65 mg (0.39
mmol) of aldehyde 5 in the presence of 23 mg (0.19 mmol) of
L-proline in 5 mL of ethyl acetate under argon at 70 °C for 3
days, 3 mL of DMF was added and the reaction mixture was
heated at the same temperature for another 3 days. After
To a dried 100 mL round-bottomed flask were added 1.19 g
(7 mmol) of AgNO3, 0.828 g (6.2 mmol) of NCS, 40 mL of
CH3CN, and 16 mL of H2O under argon, the solution was
stirred and cooled in an ice-water bath, and a solution of 0.4
g (1.55 mmol) of 25 in 10 mL of CH3CN was added dropwise
over 30 min. To this solution were added 2 mL of a saturated
aqueous solution of Na2SO3 and Na2CO3, 2 mL of a saturated
aqueous NaCl solution, and 20 mL of a 1:1 mixture of CH2Cl2-
petroleum ether sequentially at 1-min intervals. The whole
mixture was then filtered through Celite and washed with 100
mL of CH2Cl2 and petroleum ether. The filtrate was trans-
ferred into a separatory funnel, and the aqueous layer was
separated and extracted with 40 mL of CH2Cl2. The combined
organic layers were dried (MgSO4), filtered, concentrated, and
column chromatographed on silica gel using a gradient mixture
of hexane and diethyl ether as eluant to give 0.154 g (59%
yield) of pure 5: IR (neat) ν 2750, 1720, 1680 (CdO); 1H NMR
δ 10.2 (s, 1 H, CHO), 8.18 (d, J ) 0.8 Hz, 1 H, formyloxy CH),
5.53 (t, J ) 4.8 Hz, 1 H, CH-O), 2.39-2.3 (m, 1 H), 2.14 (s, 3
H, Me), 2.17-2.08, (m, 1 H), 1.94-1.6 (a series of m, 4 H); 13
C
NMR δ 191.6 (s, CdO aldehyde), 160.7 (s, C)O of formyloxy),
148.7 (s, Cd), 137.4 (s, Cd), 71.7 (d, CH-O), 28.6 (t), 22.5 (t),

One-Pot Condensation of Pyrones and Enals
J . Org. Chem., Vol. 62, No. 20, 1997 6895
aqueous workup as described in the general procedure, 131
mg of crude product was obtained. Column chromatographic
separation of this material afforded a 39% yield of formates
26A and 26B (in a ratio of 2:1) and an 11% yield of alcohols
27A and 27B (ratio of 2:1). Compounds 26A and 26B and 27A
and 27B were separated by a careful silica gel column
chromatography to give 34 mg (26% yield) of 26A, 17 mg (13%
yield) of 26B, 9 mg (7.3% yield) of 27A, and 4 mg (3.7% yield)
of 27B. Compounds 27A and 27B were probably formed from
the hydrolytic reaction with the H2O formed from the reaction.
Compound 26A: mp 160-161 °C; 1H NMR δ 9.0 (d, J ) 2 Hz,
1 H, C2′ H, pyr), 8.66 (dd, J ) 5 Hz, 2 Hz, 1 H, C6′H), 8.18 (s,
1 H, CHO), 8.09 (dt, J ) 8 Hz, 2 Hz, 1 H, C4′H), 7.39 (dd, J )
8 Hz, 5 Hz, 1 H, C5′H), 6.46 (s, 1 H, C10H), 6.26 (s, 1 H, C4H),
5.38 (dd, J ) 12 Hz, 5 Hz, 1 H, C6H), 2.42 (m, 1 H, C9H), 2.3
(m, 1 H, C9H), 2.12 (m, 1 H), 1.88 (m, 1 H), 1.7-1.52 (m, 2 H),
1.60 (s, 3 H, Me); 13C NMR δ 161.5 (s, C1), 160.1 (d, s, 2 C,
CHO & C4a), 157.1 (s, C3), 151.3 (d, C2′, pyr), 146.7 (d, C4′),
134.2 (s, C1′), 132.8 (d, C6′), 127.3 (s, C10a), 123.6 (d, C5′),
112.3 (d, C10), 99.8 (s, C9a), 98.5 (d, C4), 84.6 (s, C5a), 76.2
(d, C6), 31.3 (t), 29.1 (t), 22.9 (t), 18.9 (q, Me); MS FAB, m/ z
340 (M+1, 100%), 293, 278, 266, 240, 202, 173. Anal. Calcd
for C19H17NO5: C, 67.25; H, 5.05. Found: C, 67.07; H, 5.29.
Com p ou n d 26B: 1H NMR δ 9.0 (d, J ) 2 Hz, 1 H, C2′ H,
pyr), 8.66 (dd, J ) 5 Hz, 2 Hz, 1 H, C6′H), 8.14 (s, 1 H, CHO),
8.10 (dt, J ) 8 Hz, 2 Hz, 1 H, C4′H), 7.39 (dd, J ) 8 Hz, 5 Hz,
1 H, C5′H), 6.45 (s, 1 H, C10H), 6.31 (s, 1 H, C4H), 5.28 (broad
s, 1 H, C6H), 2.46-1.5 (a series of m, 6 H), 1.64 (s, 3 H, Me);
13C NMR δ 161.9 (s, C1), 160.3 (d, s, 2 C, CHO & C4a), 157.3
(s, C3), 151.5 (d, C2′, pyr), 147.2 (d, C4′), 133.6 (s, C1′), 133.1
(d, C6′), 127.6 (s, C10a), 123.9 (d, C5′), 112.5 (d, C10), 100.1
(s, C9a), 98.8 (d, C4), 83.5 (s, C5a), 74.5 (d, C6), 31.5 (t), 28.1
(t), 24.0 (t), 20.8 (q, Me); MS FAB, m/ z 340 (M+1, 100%). Anal.
Calcd for C19H17NO5: C, 67.25; H, 5.05. Found: C, 66.97; H,
5.12.
6.37 (s, 1 H, C10H), 6.31 (d, J ) 2 Hz, 1 H, C4H), 3.92 (m, 1
H, C6H), 3.94 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 2.53 (broad s,
1 H, OH), 2.42 (m, 1 H), 2.3 (m, 1 H), 2.08 (m, 1 H), 1.88 (m,
1 H), 1.77 (m, 1 H), 1.58 (m, 1 H), 1.49 (s, 3 H, Me); 13C NMR
δ 162.3 (s, C1), 161.6 (s, C4a), 159.5 (s, C3), 151.4 (s, C4′), 149.2
(s, C3′), 133.9 (s, C1′), 124.0 (s, C10a), 118.9 (d, C2′), 112.7 (d,
C5′), 111.0 (d, C10), 108.2 (d, C6′), 99.1 (s, C9a), 96.2 (d, C4),
85.6 (s, C5a), 73.1 (d, C6), 56.1 (q, OMe), 56.0 (q, OMe), 31.2
(t), 29.0 (t), 22.6 (t), 19.6 (q, Me); MS FAB, m/ z 371 (M + 1,
100%), 370 (M+). Anal. Calcd for C21H22O6: C, 68.10; H, 5.99.
Found: C, 68.02; H, 5.65.
cis- a n d tr a n s-3-(3,4-Dim eth oxyp h en yl)-6-(for m yloxy)-
5a -m et h yl-1H ,7H -5a ,6,8,9-t et r a h yd r o-1-oxop yr a n o[4,3-
b][1]ben zop yr a n (28A a n d 28B). From 62 mg (0.25 mmol)
of pyrone 1C and 42 mg (0.25 mmol) of aldehyde 5, 48 mg (48%
yield) of a 2:1 mixture of formyloxy derivatives 28A and 28B
and 22 mg (24% yield) of a 2:1 mixture of alcohol 29A and
29B were obtained after column chromatographic separation.
Com p ou n d 28A: IR (Nujol) ν 3080, 1690 (s, CdO), 1640,
1
1610, 1595, 1310, 1255, 1170, 1130, 1010; H NMR δ 8.20 (s,
1 H, CHO), 7.40 (dd, J ) 8 Hz, 2 Hz, 1 H, C6′H, Ph), 7.27 (d,
J ) 2 Hz, 1 H, C2′H), 6.90 (d, J ) 8 Hz, 1 H, C5′H), 6.32 (s, 1
H, C10H), 6.24 (d, J ) 2 Hz, 1 H, C4H), 5.34 (dd, J ) 12 Hz,
4.6 Hz, 1 H, C6H), 3.94 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 2.4-
1.5 (a series of m, 6 H), 1.58 (q, Me); 13C NMR δ [from a 2:1
ratio of a mixture of 28A (c) and 28B (t)] 162.3 (C1, t), 162.1
(C1, c), 161.3 (C4a, t), 161.2 (C4a, c), 160.1 (CHO, c), 160.0
(CHO, t), 159.7 (C3, c), 159.4 (C3, t), 151.2 (C4′, c), 151.1 (C4′,
t), 148.9 (C3′, c & t), 132.7 (C1′, c), 131.8 (C1′, t), 123.7 (C10a,
c & t), 118.8 (C2′, c), 118.7 (C2′, t), 112.2 (C5′, c), 112.1 (C5′,
t), 110.8 (C10, c & t), 107.8 (C6′, c), 107.8 (C6′, t), 97.9 (C9a,
c), 97.5 (C9a, t), 95.9 (C4, c), 95.7 (C4, t), 84.0 (C5a, c), 82.7
(C5a, t), 76.2 (C6, c), 74.0 (C6, t), 56.8 (OMe, c & t), 55.7 (OMe,
c and t), 30.9 (C9, c), 30.8 (C9, t), 28.8 (C7, c), 27.7 (C7, t), 22.7
(C8, c), 20.4 (C8, t), 18.5 (Me, c and t); MS FAB, m/ z 399 (M+1,
80%), 398 (M+), 352 (90%), 261, 165 (100%), 136. Anal. Calcd
for C22H22O7: C, 66.32; H, 5.57. Found: C, 66.09; H, 5.31.
Com p ou n d 27A: 1H NMR δ 9.0 (d, J ) 2 Hz, 1 H, C2′H,
pyr), 8.66 (d, J ) 4 Hz, 1 H, C6′ H), 8.10 (dt, J ) 8 Hz, 2 Hz,
1 H, C4′H), 7.39 (dd, J ) 8 Hz, 4 Hz, 1 H, C5′H), 6.51 (s, 1 H,
C10H), 6.20 (d, J ) 2 Hz, 1 H, C4H), 4.14 (dd, J ) 12 Hz, 4.4
Hz, 1 H, C6H), 2.42-1.4 (a series of m, 6 H), 1.54 (s, 3 H, Me);
13C NMR [from a mixture of 27A (c) and 27B (t)] δ 161.7 (s,
C1), 160.3 (s, C4a), 157.3 (s, C3), 151.5 (d, C2′), 147.2 (d, C4′),
135.9 (s, C1′, c), 135.5 (s, C1′, t), 133.0 (d, C6′), 127.6 (s, C10a),
123.9 (d, C5′), 112.6 (d, C10, t), 111.7 (d, C10, c), 100.0 (s, C9a),
98.8 (d, C4, c), 94.0 (s, C5a, t), 87.5 (d, C4, t), 86.3 (s, C5a, c),
76.2 (d, C6, c), 73.3 (d, C6, t), 31.8 (t, C9, c), 31.5 (t, C9, t),
31.1 (t, C7, c), 29.9 (t, C7, t), 29.3 (t, C8, c), 23.2 (t, C8, t), 23.0
(q, Me, c), 19.8 (q, Me, t). Anal. Calcd for C18H17NO4: C, 69.44;
H, 5.50. Found: C, 69.17; H, 5.21.
Com p ou n d 28B (pure): 1H NMR δ 8.15 (s, 1 H, CHO), 7.40
(dd, J ) 8 Hz, 2 Hz, 1 H, C6′H, Ph), 7.27 (d, J ) 2 Hz, 1 H,
C2′H), 6.90 (d, J ) 8 Hz, 1 H, C5′H), 6.32 (s, 1 H, C10H), 6.29
(s, 1 H, C4H), 5.28 (s, 1 H, C6H), 3.94 (s, 3 H, OMe), 3.92 (s,
3 H, OMe), 2.4-1.5 (a series of m, 6 H), 1.62 (q, Me); MS FAB,
m/ z 399 (M + 1, 80%), 398 (M+).
Ad d ition of 3 Å Molecu la r Sieves. Condensation of 11
mg (0.065 mmol) of aldehyde 5, 20 mg (0.08 mmol) of pyrone
1C, 0.10 g of 3 Å molecular sieves, and 4 mg of L-proline in 2
mL of ethyl acetate at 65 °C for 2 days gave 7.5 mg (29% yield)
of 28A, 1.6 mg (6% yield) of 28B, 5.5 mg (50% recovery) of 5,
and 12 mg of pyrone 1C.
3,5a -D im e t h y l-6-o x o -1H ,7H -5a ,6,8,9-t e t r a h y d r o -1-
oxop yr a n o[4,3b][1]-ben zop yr a n (19). To a solution of 17
mg (0.069 mmol) of a mixture of 17A and 17B in 2 mL of
CH2Cl2 under argon was added 58 mg (0.14 mmol) of 1,1,1-
triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one.11 After be-
ing stirred at 25 °C for 24 h, the reaction mixture was diluted
with 50 mL of diethyl ether, filtered through Celite, washed
with 10 mL of saturated aqueous NaHCO3, dried (MgSO4),
concentrated, and column chromatographed on silica gel using
hexane:ether (1:1) as eluant to give 14.8 mg (87% yield) of 19;
1H NMR δ 6.28 (s, 1 H, C10 H), 5.97 (s, 1 H, C4 H), 2.68-2.56
(m, 4 H), 2.22 (s, 3 H, C3-Me), 2.1 (m, 1 H), 1.7 (m,1 H), 1.64
(s, 3 H, Me); MS FAB, m/ z 247 (M + 1), 246 (M+). Anal. Calcd
for C14H14O4: C, 68.28; H, 5.73. Found: C, 68.01; H, 6.02.
Condensation of pyrone 1A with 2-methyl-3-oxo-1-cyclohex-
enecarboxaldehyde and 0.5 equiv of L-proline in ethyl acetate
at 50 °C gave a 70% yield of ketone 19, and the spectral data
are identical with those obtained from the above oxidation
reaction.
Red u ction of 19 w ith Diba l-H. Formation of Alcohol 17A.
To a cold (-60 °C) solution of 13 mg (0.053 mmol) of ketone
19 in 2 mL of THF under argon was added 42 µL (0.063 mmol)
of Dibal-H (1.5 M in toluene). After being stirred at -60 °C
for 1 h and 0 °C for 4 h, the solution was diluted with 10 mL
of water and extracted twice with CH2Cl2, and the combined
CH2Cl2 was dried (MgSO4), concentrated, and column chro-
Com p ou n d 27B: 1H NMR δ 9.0 (d, J ) 2 Hz, 1 H, C2′H,
pyr), 8.66 (d, J ) 4 Hz, 1 H, C6′ H), 8.10 (dt, J ) 8 Hz, 2 Hz,
1 H, C4′H), 7.39 (dd, J ) 8 Hz, 4 Hz, 1 H, C5′H), 6.32 (s, 1 H,
C10H), 6.20 (d, J ) 2 Hz, 1 H, C4H), 3.94 (broad s, 1 H, C6H),
2.42-1.4 (a series of m, 6 H), 1.51 (s, 3 H, Me); MS FAB, m/ z
312 (M+1, 100%).
cis- a n d tr a n s-3-(3,4-Dim et h oxyp h en yl)-5a -m et h yl-6-
h yd r oxy-1H,7H-5a ,7,8,9-t et r a h yd r o-1-oxop yr a n o[4,3-b]-
[1]ben zop yr a n (29A a n d 29B). Condensation of 0.103 g
(0.41 mmol) of pyrone 1C and 0.058 g (0.41 mmol) of hydroxy
aldehyde 4 gave a 68% yield of 29A and 29B in a ratio of 2:1.
Column chromatographic separation gave pure 29A and 29B.
Compound 29A: 1H NMR δ 7.39 (dd, J ) 8 Hz, 2 Hz, 1 H,
C6′, Ph), 7.29 (d, J ) 2 Hz, C2′H), 6.9 (d, J ) 8 Hz, 1 H, C5′H),
6.37 (s, 1 H, C10H), 6.2 (d, J ) 2 Hz, 1 H, C4H), 4.12 (dd, J )
12 Hz, 5 Hz, 1 H, C6H), 3.94 (s, 3 H, OMe), 3.93 (s, 3 H, OMe),
2.36 (m, 1 H), 2.26 (m, 1 H), 2.04 (m, 1 H), 1.82 (m, 1 H), 1.6-
1.46 (m, 2 H), 1.51 (s, 3 H, Me); 13C NMR δ 162.5 (s, C1), 161.6
(s, C4a), 158.6 (s, C3), 151.6 (s, C4′, Ph), 149.2 (s, C3′), 134.4
(s, C1′), 124.1 (s, C10a), 119.2 (d, C2′), 112.0 (d, C5′), 111.1 (d,
C10), 108.2 (d, C6′), 98.5 (s, C9a), 96.2 (d, C4), 86.9 (s, C5a),
76.3 (d, C6), 56.3 (q, OMe), 53.6 (q, OMe), 31.7 (t), 31.1 (t),
23.3 (t), 17.6 (q, Me); MS FAB, m/ z 371 (M+1, 100%), 370
(M+), 355, 325, 307, 261, 219, 207. Anal. Calcd for C21H22O6:
C, 68.10; H, 5.99. Found: C, 67.89; H, 5.73.
Com p ou n d 29B: 1H NMR δ 7.38 (dd, J ) 8 Hz, 2 Hz, 1 H,
C6′, Ph), 7.29 (d, J ) 2 Hz, C2′H), 6.9 (d, J ) 8 Hz, 1 H, C5′H),

6896 J . Org. Chem., Vol. 62, No. 20, 1997
Hua et al.
matographed on silica gel to give 11.3 mg (87% yield) of 17A
and 1.2 mg (9% yield) of 17B.
rial Award), BioServe Space Technologies (NASA grant
NAGW-1197), and the Center for Basic Cancer Research
at KSU.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from American Heart Association,
Kansas Affiliate (KS-96-GS-69), Research Corporation
for a Research Opportunity Award (RA0203; Bristol-
Myers Squibb Company donor), NSF EPSCoR program
(CRINC 12045-46), Special Group Incentive Research
Award from Kansas State University (KSU), the Skin
Cancer Foundation, New York (Henry W. Menn Memo-
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawing of
X-ray crystallographically determined structure of 18A (1
page). 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 O970642D