Total synthesis of (±)-leporin A

Article abstract of DOI:10.1021/jo952053i

An efficient synthesis of (±)-leporin A (1) has been developed using a tandem Knoevenagel condensation-inverse electron demand intramolecular hetero Diels-Alder reaction to construct the key tricyclic intermediate 3 from pyridone 5 and dienal 6 in one pot in 35% yield. Hydroxylation (71%) of 3 and methylation (77%) of the resulting hydroxypyridone 2 completed the first total synthesis of (±)-leporin A (1).

Full text of DOI:10.1021/jo952053i

J . Org. Chem. 1996, 61, 2839-2844
2839
Tota l Syn th esis of (()-Lep or in A
Barry B. Snider* and Qing Lu
Department of Chemistry, Brandeis University, P.O. Box 9110, Waltham, Massachusetts 02254
Received November 21, 1995X
An efficient synthesis of (()-leporin A (1) has been developed using a tandem Knoevenagel
condensation-inverse electron demand intramolecular hetero Diels-Alder reaction to construct
the key tricyclic intermediate 3 from pyridone 5 and dienal 6 in one pot in 35% yield. Hydroxylation
(
71%) of 3 and methylation (77%) of the resulting hydroxypyridone 2 completed the first total
synthesis of (()-leporin A (1).
7
In tr od u ction
at reflux for 60 h afforded 46% of Diels-Alder adduct
0, 28% of the desired ene adduct 11, and 25% of Diels-
1
Gloer and co-workers recently isolated the antiinsectan
leporin A (1) from the sclerotia of Aspergillius leporis
5
Alder adduct 12. The formation of o-quinone methide
and the inverse electron demand hetero Diels-Alder
9
(
2
NRRL 3126) and determined its structure by 1D- and
reaction to give tricycle 10 is analogous to the proposed
conversion of 5 and 6 to 4 and then 3.
1
D-NMR experiments. Leporin A exhibits moderate
activity against the corn earworm Helicoverpa zea, caus-
ing 35.6% reduction in growth rate when incorporated
into a standard test diet at a 100 ppm concentration; it
also exhibits mild antibacterial activity against Bacillus
subtilis.1
We envisaged that a synthesis of leporin A (1) could
be carried out by Knoevenagel condensation of 4-hydroxy-
-phenyl-2-pyridone (5) with 2-methyl-6E,8E-decadienal
The conversion of 9 to 10 and the proposed conversion
of 4 to 3 differ in the substitution pattern of the
dienophile in 4 and 9 and the ring fusion stereochemistry
in the hetero Diels-Alder adducts 3 and 10. The hetero
Diels-Alder and ene reactions fail with the less nucleo-
philic 1,2-disubstituted alkene of 13; use of the more
nucleophilic allylsilane 14 was necessary for the synthe-
sis of pyridoxatin intermediate 15. However, the conju-
gated diene of 4 should make the 1,2-disubstituted double
bond of 4 more nucleophilic than the trisubstituted
double bond of 9 so that 3 should be formed. More
troubling was the formation of 10 with a trans ring fusion
and the formation of the trans ring fusion as the exclusive
or major product in all of Tietze’s studies with aliphatic
5
(
6), to give the unstable o-quinone methide 4, which
should undergo an inverse electron demand intramolecu-
lar Diels-Alder reaction with the quinone methide
functioning as the diene and the acyclic diene functioning
as the dienophile to give the tricyclic intermediate 3.
Tandem Knoevenagel condensation-inverse electron de-
mand intramolecular hetero Diels-Alder reactions of this
type have been extensively developed by Tietze. N-
Hydroxylation of 3 to give 2 followed by O-methylation
of 2 would complete the synthesis of leporin A.
2
aldehydes, while the synthesis of leporin A will require
2
the formation of 3 with a cis ring fusion. Although we
were comforted by molecular mechanics calculations that
suggested that the change from the trisubstituted alkene
of 9 to the trans disubstituted alkene of 4 would favor
the desired cis ring fusion, the stereochemistry of the
hetero Diels-Alder reaction remained a major concern
that could only be answered by experimentation.
3
4
Resu lts a n d Discu ssion
Condensation of phenylacetonitrile with malonyl chlo-
ride provided 58% of chloropyridone 17.8 Hydrogenolysis
9
2
(1 atm H ) over Pd/C in EtOH at 60 °C formed 98% of
(2) (a) Teitze, L. F. Chem. Ind. 1995, 453. (b) Teitze, L. F.; Beifuss,
U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (c) Tietze, L. F. J .
Heterocycl. Chem. 1990, 27, 47. (d) Tietze, L. F.; Geissler, H.; Fennen,
J .; Brumby, T.; Brand, S.; Schulz, G. J . Org. Chem. 1994, 59, 182. (e)
Tietze, L. F.; Brand, S.; Brumby, T.; Fennen, J . Angew. Chem., Int.
Ed. Engl. 1990, 29, 665.
(3) (a) Matlin, S. A.; Sammes, P. G.; Upton, R. M. J . Chem. Soc.,
Perkin. Trans. 1 1979, 2481. (b) Rigby, J . H.; Qabar, M. J . Org. Chem.
1
989, 54, 5852.
4) (a) Cook, M. J .; Katritzky, A. R.; Millet, G. H. Heterocycles 1977,
(
The proposed one-pot conversion of pyridone 5 and
dienal 6 to tricyclic intermediate 3 is well-precedented
in our model study for the synthesis of pyridoxatin (16),5
a free-radical scavenger isolated from Acremonium sp.
BX86.6 Reaction of 4-hydroxy-2-pyridone (7) with cit-
ronellal (8) in EtOH containing piperidine and pyridine
7
, 227. (b) Gardner, J . N.; Katritzky, A. R. J . Chem. Soc. 1957, 4375.
(5) (a) Snider, B. B.; Lu, Q. Tetrahedron Lett. 1994, 35, 531. (b)
Snider, B. B.; Lu, Q. J . Org. Chem. 1994, 59, 8065.
6) Teshima, Y.; Shin-ya, K.; Shimazu, A.; Furihata, K.; Chul, H.
S.; Furihata, K.; Hayakawa, Y.; Nagai, K.; Seto, H. J . Antibiot. 1991,
44, 685.
7) Findlay, J . A.; Krepinsky, J .; Shum, F. Y.; Tam, W. H. J . Can.
J . Chem. 1976, 54, 270.
8) Buck, J .; Madeley, J . P.; Pattenden, G. J . Chem. Soc., Perkin
(
(
(
X
Abstract published in Advance ACS Abstracts, April 1, 1996.
Trans. 1 1992, 67.
(
1) TePaske, M. R.; Gloer, J . B.; Wicklow, D. T.; Dowd, P. F.
(9) (a) Hung, N. C.; Bisagni, E. Synthesis 1984, 765. (b) Davis, S.
J .; Elvidge, J . A.; Foster, A. B. J . Chem. Soc. 1962, 3638.
Tetrahedron Lett. 1991, 32, 5687.
0
022-3263/96/1961-2839$12.00/0 © 1996 American Chemical Society

2
840 J . Org. Chem., Vol. 61, No. 8, 1996
Snider and Lu
the desired cis fused tricyclic inverse electron demand
hetero Diels-Alder adduct 3, the trans fused diastere-
omer 21, and two spiro fused Diels-Alder adducts 22 and
2
3, which could be formed from the quinone methide
acting as the dienophile in a normal Diels-Alder reac-
tion. Similar, poorly reproducible results were obtained
in dioxane, MeOH, and with pyridine, piperidine, or
mixtures of both bases. The yield of 3 was highest when
most of the EtOH evaporated during the reaction.
the requisite pyridone 5.10 Hydrogenolysis at 25 °C was
unsuccessful because of the limited solubility of 17 in
EtOH.
Ring opening of 2-methylbutyrolactone with HBr in
ethanol (96%) and reduction of the bromo ester with LAH
in ether at 0 °C (75%) gave 4-bromo-2-methyl-1-butanol
18).11 Protection of the alcohol (dihydropyran, CH
2 2
Cl ,
From this observation we developed reproducible con-
ditions that led to acceptable yields of 3. A mixture of 5
(
TsOH) afforded 68% of THP ether 19. Reaction of 19
with Mg in THF provided the Grignard reagent, which
(
1.6 equiv), Et
stirred under N
3
N (2 equiv), and 6 (0.2 M in EtOH) was
for 2 h and placed in an oil bath that
was added to a mixture of Li
2
4
CuCl and 2E,4E-hexadien-
2
was heated to 160 °C. The oil bath was kept at 160 °C
for 20 h during which time most of the EtOH evaporated
from the solution. This protocol afforded 35% of 3, 7%
of 21, and 32% of an inseparable ≈1:1 mixture of 22 and
a diastereomer 23, whose stereochemistry was not as-
signed.
1
-yl acetate in THF to give 44% of dienol 20 after acid
1
2
hydrolysis of the THP ether. Swern oxidation gave 79%
of dienal 6 completing the synthesis of the second
coupling component.
Spiro adducts 22 and 23 could be formed by a normal
1
3
Diels-Alder reaction of 4 or by Claisen rearrangement
of the inverse electron demand hetero Diels-Alder ad-
ducts 3 and 21. Heating trans fused adduct 21 in EtOH
at reflux for 12 h gave 65% conversion to spiro adduct
2
2 with 20% recovered 21 indicating that the Claisen
rearrangement occurs under the conditions used for the
condensation of 5 and 6. On the other hand, the desired
cis fused adduct 3 was completely stable under these
The condensation of 5 and 6 in EtOH containing
piperidine and pyridine5 afforded variable amounts of
,7
(
10) Streef, J . W.; den Hertog, H, J .; van der Plas, H. C. J . Heterocycl.
Chem. 1985, 22, 985.
(13) (a) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515.
(b) Danishefsky, S.; Audia, J . E. Tetrahedron Lett. 1988, 29, 1371. (c)
B u¨ chi, G.; Powell, J . E., J r. J . Am. Chem. Soc. 1970, 92, 3126. (d)
Danishefsky, S.; Funk, R. L.; Kerwin, J . F., J r. J . Am. Chem. Soc. 1980,
102, 6889.
(
(
11) Collins, D. J .; J ames, A. M. Aust. J . Chem. 1989, 42, 223.
12) (a) Samain, D.; Descoins, C.; Commer c¸ on, A. Synthesis 1978,
3
88. (b) Bailey, S. J .; Thomas, E. J .; Turner, W. B.; J arvis, J . A. J . J .
Chem. Soc., Chem. Commun. 1978, 474.

Total Synthesis of (()-Leporin A
J . Org. Chem., Vol. 61, No. 8, 1996 2841
conditions. Therefore the 5:1 ratio of 3 and 21 isolated
from the condensation of 5 and 6 does not reflect the
kinetic preference of the inverse electron demand hetero
Diels-Alder reaction, but simply the instability of 21
under the reaction conditions.
given a diastereomer of 22 with the methyl group trans
to the ketone carbonyl group and H
c
. The stereochem-
istry of the other diastereomer 23, which could not be
obtained pure, was not assigned. The first total synthesis
of (()-leporin A (1) was completed by silylation of 3 with
1
4
The stereochemistry of 3 and 21 was easily established
TMSCl and HMDS and oxidation with MoO
5
‚pyr‚HMPA
3
by analysis of the coupling constants. In 3, H
at δ 2.79 (dd, J bc ) 3.7 Hz, J cd ) 10.9 Hz). The large
coupling between H and H indicated that these hydro-
gens are trans and axial on the cyclohexane, while the
c
absorbs
in CH Cl at rt as described by Sammes to provide the
2 2
molybdenum salt of 2. Washing with tetrasodium EDTA
solution removed the molybdenum to give 57% (71%
based on recovered 3) of hydroxypyridone 2. Methylation
c
d
4
small coupling between H
equatorial on the cyclohexane. H
b
and H
c
established that H
absorbs at δ 4.58 (dd,
b
is
of 2 with NaOMe and MeI in methanol afforded 77% of
a
(()-leporin A (1), whose spectral data and chromato-
graphic properties are identical with those of a natural
sample provided by Prof. Gloer.
J
H
ab ) 11.3, J a,CHd ) 8.1 Hz). The large coupling between
and H showed that these hydrogens are trans and
axial on the dihydropyran. These coupling constants are
very similar to those reported for leporin A.1 In 21, H
absorbs at δ 2.39 (dd, J bc ) 10.0 Hz, J cd ) 10.0 Hz). The
large coupling between H and H , and H and H
established that all three hydrogens are trans and axial
on the cyclohexane. H absorbs at δ 3.95 (dd, J ab ) 10.0,
a,CHd ) 7.7 Hz). The large coupling between H and H
a
b
The key intermediate 4 underwent competing inverse
electron demand intramolecular hetero Diels-Alder re-
actions to give 3 and 21 and normal intramolecular
Diels-Alder reactions to give 22 and 23. This is not the
ideal system to study these competing reactions since the
asymmetry of the carbonyl groups of 4 and the methyl
group on the tether complicated the stereochemical
analysis of the products. Furthermore, the intramolecu-
lar hetero Diels-Alder adduct 21 undergoes a Claisen
rearrangement to give 22 at the high temperature
required for the Knoevenagel condensation that produces
o-quinone methide 4, so that 22 can be formed by both a
normal Diels-Alder reaction and Claisen rearrangement
of hetero Diels-Alder adduct 21.
c
b
c
c
d
a
J
a
b
indicated that these hydrogens are trans and diaxial on
the dihydropyran.
A total of four inverse electron demand hetero Diels-
Alder adducts could have been formed from addition of
the acyclic diene to the enone of 4. As has been observed
in related reactions,2 the two diastereomers of 3 and
d,e
2
c
1 with H trans to the methyl group were not formed.
There are severe steric interactions between the methyl
group and the carbonyl groups of the quinone methide 4
in the transition state for the hetero Diels-Alder reac-
To study these competing Diels-Alder reactions in
simpler systems at lower temperatures, we prepared
aldehyde 27 analogously to 6 and condensed it at 25 °C
with the symmetrical dicarbonyl compounds extensively
studied by Tietze.2 Protection of 4-bromobutanol (24)
a b
tions leading to these diastereomers. H and H must
be trans in all four possible inverse electron demand
hetero Diels-Alder adducts since a concerted cycloaddi-
tion results in cis addition to the trans double bond of
the dienophile.
Four additional hetero Diels-Alder adducts could have
been formed by inverse electron demand hetero Diels-
Alder addition to the enamide, rather than the enone, of
(dihydropyran, CH
ether 25. Reaction of 25 with Mg in THF provided the
Grignard reagent, which was added to a mixture of Li
CuCl and 2E,4E-hexadien-1-yl acetate in THF to give
2 2
Cl , TsOH) provided 70% of the THP
2
-
4
25% of dienol 26 after acid hydrolysis. Swern oxidation
afforded 92% of dienal 27.
4
as in the formation of 12 from 9. Analysis of UV
Condensation of dienal 27 with 5,5-dimethylcyclohex-
ane-1,3-dione (28) and ethylenediammonium diacetate in
spectra is the most reliable technique for distinguishing
2
2
2
-pyridones from 4-pyridones. 2-Pyridone 10 absorbs at
CH Cl for 12 h at 25 °C as described by Tietze afforded
2
2
5
81 nm while 4-pyridone 12 absorbs at 258 nm. Use of
only 5% of the inverse electron demand hetero Diels-
Alder adduct 30 and 61% of a partially separable 2:1
mixture of normal Diels-Alder adducts 31 and 32. The
UV spectral data to establish the structures of 3 and 21
was complicated by the phenyl substituent which domi-
nates the UV spectra. 5-Phenyl-4-methoxy-2-pyridones
absorb at 235-250 nm with a much weaker absorption
at 290-300 nm, while 5-phenyl-2-methoxy-4-pyridones
absorb at 225-235 nm with a much weaker absorption
at 255-260 nm.8 Hetero Diels-Alder adducts 3 and 21
absorb at 240 nm with a strong shoulder at 290-300 nm,
indicating that they are 2-pyridones. It is possible that
a hetero Diels-Alder adduct analogous to 12 was formed
and reacted further by a Claisen rearrangement to give
allylic ring fusion hydrogen H of 30 absorbs at δ 2.87
c
with only one large axial-axial coupling establishing that
the ring fusion is cis. The allylic ring fusion hydrogen
(H ) of 31 absorbs at δ 2.70 ppm with two large axial-
b
axial couplings establishing that the ring fusion is trans.
No Claisen rearrangement occurred on heating 30 for 12
h in ethanol at reflux so that 32 is formed by a normal
Diels-Alder reaction rather than a hetero Diels-Alder
reaction followed by a Claisen rearrangement. Since the
condensation is carried out at 25 °C, 31 is also probably
formed directly by a normal Diels-Alder reaction. Simi-
lar condensation of dienal 27 with 1,3-dimethylbarbituric
acid or Meldrum's acid gave only the normal Diels-Alder
adducts. The absence of significant amounts of hetero
Diels-Alder adducts in these condensations precludes
further study of the Claisen rearrangement or of the
effect of double bond substitution pattern on ring fusion
stereochemistry of the hetero Diels-Alder reaction.
Presumably, the hetero Diels-Alder adducts 3 and 21
are signficant products from O-quinone methide 4 since
2
3.
The structure of 22 was established by its formation
from 21 by a Claisen rearrangement, which must proceed
through a boat transition state since the allyl vinyl ether
1
3
is a vinyldihydropyran.
cyclohexane ring was confirmed by the absorption for H
at δ 2.02 (dd, 1, J bc ) 10.5 Hz, J cd ) 10.5 Hz), which
indicates that H , H , and H are trans and axial on the
cyclohexane ring. Rearrangement of 21 through a boat
transition state will give 22 with the methyl group and
The stereochemistry of the
c
b
c
d
c
the ketone carbonyl group cis to H on the cyclohexene
ring. Reaction through a chair transition state, which
is precluded by geometric considerations,13 would have
(14) Vedejs, E.; Larsen, S. Org. Synth. 1989, 64, 127.

2
842 J . Org. Chem., Vol. 61, No. 8, 1996
Snider and Lu
evaporated under reduced pressure to give 2.9 g (98%) of
pyridone 5 as a buff solid which was recrystallized from
EtOAc: mp 179-180 °C (lit.10 mp 171-177 °C); H NMR (CD
1
-
3
1
3
OD) 7.86 (s, 1), 7.52-7.41 (m, 5), 6.51 (s, 1); C NMR 171.7,
63.2, 137.8, 133.6, 130.4 (2 C), 129.7 (2 C), 129.6, 122.6, 97.9;
IR (KBr) 3423, 2956, 1642, 1420; UV (MeOH) λmax nm (ꢀ) 295
6,000, sh), 238 (41,300).
-Br om o-2-m eth ylbu ta n -1-ol (18).11 2-Methylbutyrolac-
1
(
4
tone (5.3 g, 53 mmol) was added to a freshly prepared
saturated solution of dry hydrogen bromide in absolute ethanol
(50 mL). The solution was stirred at rt for 3 d, poured into
ice-water, and extracted with ether (3 × 100 mL). The
combined organic extracts were washed with saturated NaH-
3 4
CO solution (100 mL) and water (100 mL), dried (MgSO ),
and concentrated under reduced pressure to give 10.7 g (96%)
of ethyl 4-bromo-2-methylbutyrate.
A solution of the above ester (10 g, 47.8 mmol) in dry ether
(
50 mL) was added dropwise over 30 min to a suspension of
LAH (1.9 g, 47.8 mmol) in dry ether (100 mL) at 0 °C under
. The reaction mixture was stirred for 2 h at 0 °C. Methanol
1 mL) was added dropwise to the suspension, and the mixture
was poured into ice-cold 2 N HCl solution (200 mL). The
mixture was extracted with ether, which was dried (MgSO
N
2
(
4
)
and concentrated to give 6 g (75%) of 18, whose spectral data
are identical to those previously described.11
4
-Br om o-2-m eth ylbu tyl Tetr a h yd r op yr a n yl Eth er (19).
A solution of dihydropyran (3.4 mL, 36.9 mmol), alcohol 18
5.6 g, 33.5 mmol), and a catalytic quantity of p-TsOH (14 mg)
in CH Cl (50 mL) was stirred at rt for 2 h. A few drops of
Et N were added, and the mixture was evaporated under
(
2
2
the aromatic stabilization of the products is reflected in
lower transition state energies, while the normal Diels-
Alder products 22 and 23 are not aromatic. The hetero
Diels-Alder adducts, e.g. 30, formed from 5,5-dimethyl-
cyclohexane-1,3-dione, 1,3-dimethylbarbituric acid, and
Meldrum’s acid are not aromatic so the normal Diels-
Alder adducts, e.g. 31 and 32 are the major or exclusive
product.
A short and efficient synthesis of leporin A has been
developed using a tandem Knoevenagel condensation-
inverse electron demand intramolecular hetero Diels-
Alder reaction to construct the key tricyclic intermediate
3
reduced pressure. Filtration through a short silica gel plug
eluting with hexane, followed by flash chromatography on
1
silica gel (10:1 hexane-EtOAc) gave 5.5 g (68%) of 19:
H
NMR 4.58-4.55 (m, 1), 3.87-3.80 (m, 1), 3.60 (ddd, 1, J ) 9.5,
8
1
.2, 6.2), 3.53-3.42 (m, 3), 3.24 (ddd, 1, J ) 9.5, 8.5, 5.7), 2.10-
.91 (m, 2), 1.86-1.44 (m, 7), 0.96 (d, 0.5 × 3, J ) 6.7), 0.95
13
(
d, 0.5 × 3, J ) 6.7); C NMR (99.0, 98.8), (72.2, 72.1), (62.2,
62.1), (37.2, 37.1), (32.4, 32.3), (32.0, 31.9), 30.6, 25.6, (19.5,
19.4), (16.6, 16.5); IR (neat) 2942, 2872, 1448, 1260, 1201.
2
-Meth yl-6E,8E-d eca d ien ol (20). To a suspension of Mg
(
(
1.2 g, 47.8 mmol) in 19 mL of THF was added dibromoethane
0.5 mL). When all the dibromoethane had reacted, the gray
solution was removed by syringe. After rinsing the Mg with
THF (20 mL) twice, 20 mL of THF was added. Bromide 19
3
in one pot in 35% yield from the readily available
pyridone 5 and dienal 6. A similar process may occur in
the biosynthesis of leporin A. The formation of the cis
fused product 3 as the major product with the E,E-diene
as the dienophile is particularly noteworthy since the
(
4.8 g, 19.1 mmol) was added dropwise to the Mg suspension.
The mixture was stirred at rt for 2 h. This gray solution was
then added dropwise under N to a cooled (-10 °C) solution of
2E,4E-hexadien-1-yl acetate (2.3 g, 16.2 mmol) and Li CuCl
6.48 mL, 0.1 M in THF) in THF (20 mL). The color changed
2
2
4
(
trans fused products 10 and 12 are formed exclusively
with trisubstituted alkenes as the dienophile.2,5 This first
from orange to dark brown to green and finally to purple. The
resulting mixture was held at 0 °C for 2 h and then at rt
overnight. Saturated NH Cl was added, and the mixture was
4
extracted with ether. The ether layers were evaporated under
reduced pressure. The crude oily residue was dissolved in
methanol (30 mL) containing p-TsOH (518 mg, 2.7 mmol) and
synthesis provides (()-leporin A in only ten steps from
inexpensive commercially available starting materials,
with a longest linear sequence of eight steps, in 4%
overall yield.
stirred for 2 h at rt. Et N (330 µL, 2.4 mmol) was added, and
3
the solvent was removed under reduced pressure. The residue
was dissolved in ether, which was washed with 0.1 N HCl and
Exp er im en ta l Section
Gen er a l. NMR spectra were recorded at 300 MHz in CDCl
unless otherwise indicated; chemical shifts are reported in δ
and coupling constants in Hz.
3
4
water and then dried (MgSO ). Removal of the solvent and
flash chromatography of the residue on silica gel (5:1 hexane-
EtOAc) gave 1.5 g (44%) of 20: 1H NMR 6.03 (dt, 1, J ) 14.5,
1.1), 6.06-5.96 (m, 1), 5.64-5.50 (m, 2), 3.50 (dd, 1, J ) 10.5,
5.8), 3.41 (dd, 1, J ) 10.5, 6.5), 2.05 (ddd, 2, J ) 6.6, 6.6, 6.6),
1.73 (d, 3, J ) 6.5), 1.68-1.58 (m, 2), 1.46-1.32 (m, 2), 1.16-
1.08 (m, 1), 0.91 (d, 3, J ) 6.8); 13C NMR 132.0, 131.8, 130.6,
127.1, 68.5, 35.9, 33.0, 32.9, 27.0, 18.2, 16.7; IR (neat) 3346,
6
-Ch lor o-4-h yd r oxy-5-p h en yl-2(1H)-p yr id on e (17) was
8
prepared by the literature procedure. Malonyl dichloride (8
mL, 82 mmol) and phenylacetonitrile (4.5 mL, 39 mmol) were
stirred together under anhydrous conditions for 4 d. Diethyl
ether (25 mL) was added, and the precipitated 17 was filtered
and washed with diethyl ether. Recrystallization from EtOAc
gave 5 g (58%) of pyridone 17 as a buff solid: mp 300-302 °C
3015, 2928, 1461. Anal. Calcd for C11
Found: C, 77.73; H, 12.06.
H20O: C, 78.58; H, 11.90.
8
1
(
7
1
lit. mp 297-299 °C); H NMR (CD
3
SOCD
.47-7.22 (m, 5), 6.17 (s, 1); 13C NMR 166.3, 162.9, 145.6,
34.0, 130.7 (2 C), 128.0 (2 C), 127.4, 117.2, 94.3.
-H yd r oxy-5-p h en yl-2(1H )-p yr id on e (5). Chloropyri-
done 17 (3.5 g, 15.8 mmol) and 10% palladium on charcoal
580 mg) in absolute EtOH (150 mL) were heated at 60 °C
3
) 10.98 (br s, 2),
2-Meth yl-6E,8E-d eca d ien a l (6). Dimethyl sulfoxide (0.23
mL, 3.2 mmol) was added slowly to a solution of oxalyl chloride
(0.14 mL, 1.6 mmol) in 5 mL of dry CH
mixture was stirred for 20 min, and a solution of alcohol 20
(177 mg, 1.0 mmol) in 1 mL of CH Cl was added slowly to
the mixture, which was then stirred at -78 °C for 20 min.
Et N (0.90 mL, 6.4 mmol) was added slowly to the mixture,
which was then warmed to rt. Ether was added, and the
2 2
Cl at -78 °C. The
4
2
2
(
under a hydrogen atmosphere for 40 h. The catalyst was
filtered off and washed with hot ethanol. The solvent was
3

Total Synthesis of (()-Leporin A
J . Org. Chem., Vol. 61, No. 8, 1996 2843
solution was washed with water, dried (MgSO
trated under reduced pressure. Flash chromatography of the
4
), and concen-
at 100 °C for 12 h. No reaction occurred as determined by
analysis of the NMR spectrum.
residue on silica gel (10:1 hexane-EtOAc) gave 139 mg (79%)
(6r(E),6a r,10r,10a r)-2,6,6a ,7,8,9,10,10a -Oct a h yd r o-2-
h yd r oxy-10-m et h yl-4-p h en yl-6-(1-p r op en yl)-1H -[2]b en -
zop yr a n o[4,3-c]p yr id in -1-on e (2). HMDS (1.0 mL, 6.2
mmol) containing chlorotrimethylsilane (0.5 mL) was added
to pyridone 3 (25 mg, 0.03 mmol). The solution was heated
1
of 6 as a colorless oil: H NMR 9.60 (d, 1, J ) 1.9), 6.06-5.95
(m, 2), 5.6-5.47 (m, 2), 2.33 (dtq, 1, J ) 1.9, 6.9, 6.9), 2.07 (dt,
2
1
1
1
, J ) 6.9, 6.9), 1.73 (d, 3, J ) 6.3), 1.73-1.66 (m, 1), 1.47-
.35 (m, 3), 1.08 (d, 3, J ) 6.9); 13C NMR 205.3, 131.7, 131.2,
31.0, 127.4, 46.4, 32.6, 30.1, 26.9, 18.2, 13.5; IR (neat) 3016,
726.
at reflux for 6 h under N
2
, and the excess HMDS was removed
under reduced pressure. The residue was treated with oxo-
(
6r(E),6a r,10r,10a r)-2,6,6a ,7,8,9,10,10a -Octa h yd r o-10-
diperoxymolybdenum-pyridine-HMPA complex (65 mg, 0.15
m eth yl-4-p h en yl-6-(1-p r op en yl)-1H-[2]ben zop yr a n o[4,3-
c]p yr id in -1-on e (3), (6r(E),6a r,10â,10a â)-2,6,6a ,7,8,9,10,-
0a -Oct a h yd r o-10-m et h yl-4-p h en yl-6-(1-p r op en yl)-1H -
2 2
mmol) in dry CH Cl at rt overnight by the procedure of
Sammes.3 Removal of the solvent under reduced pressure
followed by flash chromatography of the residue on silica gel
(EtOAc) gave the molybdenum complex of 2, followed by 5 mg
(19%) of recovered 3. The molybdenum complex of 2 was
dissolved in EtOAc (3 mL) and stirred with saturated aqueous
tetrasodium EDTA solution (3 mL) for 2 h. The mixture was
neutralized with 0.1 M HCl solution. The layers were sepa-
rated, and the organic layer was washed with water, dried
1
[
8
2]b en zop yr a n o[4,3-c]p yr id in -1-on e (21), a n d 4a ,5,6,7,-
,8a ,1′,4′-Oct a h yd r o-2,5-d im et h yl-5′-p h en ylsp ir o[n a p h -
th a len e-1(2H),3′(2′H)-p yr id in e]-2′,4′-d ion e (22 a n d 23). A
solution of pyridone 5 (39 mg, 0.21 mmol), Et N (35 µL, 0.25
mmol), and aldehyde 6 (22.8 mg, 0.13 mmol) in absolute EtOH
0.6 mL) was stirred at rt for 2 h and placed in an oil bath
which was heated to 160 °C over 30 min. The oil bath was
kept at 160 °C for 20 h under N Most of the solvent
3
(
4
(MgSO ), and concentrated under reduced pressure to give a
white solid that was washed with EtOAc to give 15.0 mg (57%,
2
.
evaporated during this time. If the ethanol did not evaporate,
the yield of 22 and 23 increased at the expense of 3 and 21.
The solvent was removed under reduced pressure. The
combined residue from three reactions (a total of 78.8 mg of
aldehyde 6) was purified by flash chromatography on silica
gel (EtOAc) giving 48 mg (32%) of a 1:1 mixture of 22 and 23
as a brown, waxy solid, followed by 10 mg (7%) of 21 as a white
solid, followed by 53 mg (35%) of 3 as a white powder. 3 and
71% based on recovered 3) of pure 2 as a white solid: mp 117-
1
118 °C; H NMR 7.61 (s, 1), 7.44-7.28 (m, 5), 5.74 (dq, 1, J )
15.1, 6.6), 5.38 (ddq, 1, J ) 15.1, 8.3, 1.5), 4.82 (dd, 1, J )
11.1, 8.3), 2.80 (dd, 1, J ) 10.7, 3.6), 1.73 (dd, 3, J ) 6.6, 1.5),
1.80-1.23 (m, 8), 0.91 (d, 3, J ) 6.5); 13C NMR 158.2, 157.5,
133.6, 131.0, 129.3, 129.2, 129.1 (2 C), 128.2 (2 C), 127.3, 113.4,
111.0, 78.1, 38.0, 35.8, 35.7, 35.1, 26.4, 20.8, 20.3, 17.8; IR
(neat) 2945, 1637, 1497, 1219, 942; UV (MeOH) λmax nm (ꢀ)
300 (5 500, sh), 241 (25 100); (MeOH + HCl) 235 (28 000);
(MeOH + NaOH) 330 (6 400, sh), 282 (12 300), 241 (22 900).
(6r(E),6a r,10r,10a r)-2,6,6a ,7,8,9,10,10a -Oct a h yd r o-2-
m et h oxy-10-m et h yl-4-p h en yl-6-(1-p r op en yl)-1H -[2]b en -
zop yr a n o[4,3-c]p yr id in -1-on e (Lep or in A, 1). NaOMe (1
mL, 0.5 M in MeOH) and MeI (0.3 mL, 4.8 mmol) were added
to N-hydroxypyridone 2 (10 mg, 0.028 mmol). The mixture
was heated at 55 °C for 2 h. The solvent was removed under
reduced pressure, and the residue was dissolved in EtOAc and
washed with water three times. The layers were separated,
2
2 2
1 were recrystallized from CH Cl /EtOAc.
Analysis of the NMR spectra indicated that an inseparable
1
:1 mixture of 22 and 23 was present. Partial data for 23:
1
H NMR 5.82 (ddd, 1, J ) 9.3, 2.7, 2.7), 1.11 (d, 3, J ) 7.3),
0
.75 (d, 3, J ) 6.4).
1
Data for 21: mp 203-205 °C; H NMR 7.44-7.26 (m, 5),
.16 (s, 1), 5.67 (dq, 1, J ) 15.0, 6.6), 5.44 (ddq, 1, J ) 15.0,
.7, 1.5), 3.95 (dd, 1, J ) 10.0, 7.7), 2.39 (dd, 1, J ) 10.0, 10.0),
.86-1.06 (m, 8), 1.70 (dd, 3, J ) 6.6, 1.5), 1.19 (d, 3, J ) 6.5);
C NMR 165.5, 163.7, 134.3, 131.0, 130.3, 129.0 (2 C), 128.6,
28.1 (2 C), 126.9, 115.6, 112.0, 83.2, 47.7, 44.3, 40.5, 36.5,
9.1, 25.9, 22.9, 17.8; IR (neat) 2928, 1641, 1600, 1447, 1229;
7
7
1
1
3
1
2
2 4
and the organic layer was dried (Na SO ) and concentrated
under reduced pressure. Flash chromatography of the residue
UV (MeOH) λmax nm (ꢀ) 300 (7 500, sh), 240 (31 000), 201
on silica gel (4:1 hexane-EtOAc) gave 8 mg (77%) of leporin
1
(43 700); (MeOH + HCl) 236 (34 600), 202 (51 100); (MeOH +
A (1): mp 168-169 °C; H NMR 7.43-7.31 (m, 5), 7.38 (s, 1),
NaOH) 300 (6 400, sh), 240 (29 900).
5.75 (dq, 1, J ) 15.2, 6.5); 5.37 (ddq, 1, J ) 15.2, 8.1, 1.5), 4.82
(dd, 1, J ) 11.1, 8.1), 4.06 (s, 3), 2.84 (dd, 1, J )10.7, 3.8),
1.73 (dd, 3, J ) 6.5, 1.5), 1.82-1.24 (m, 8), 1.00 (d, 3, J ) 6.6);
1
Data for 3: mp 228-229 °C; H NMR 7.43-7.28 (m, 5), 7.21
(
1
(
s, 1), 5.76 (dq, 1, J ) 15.2, 6.5), 5.39 (ddq, 1, J ) 15.2, 8.1,
1
3
.5), 4.58 (dd, 1, J ) 11.3, 8.1), 2.79 (dd, 1, J ) 10.9, 3.7), 1.72
dd, 3, J ) 6.5, 1.5), 1.83-1.26 (m, 8), 1.01 (d, 3, J ) 6.5); 13
NMR 165.2, 160.5, 134.7, 131.8, 131.0, 129.7, 129.3 (2 C), 128.3
2 C), 127.2, 115.3, 111.7, 78.3, 37.3, 36.2, 36.1, 35.4, 26.7, 21.1,
0.7, 18.0; IR (neat) 2925, 1643, 1454, 1218; UV (MeOH) λmax
nm (ꢀ) 295 (4 400, sh), 240 (23 600); (MeOH + HCl) 235
26 200); (MeOH + NaOH) 295 (6 400, sh), 240 (22 000). Anal.
Calcd for C22 : C, 78.77; H, 7.51, N, 4.18. Found: C,
8.56; H, 7.69; N, 4.17.
Cla isen Rea r r a n gem en t of 21 to 22. A solution of 21
10 mg, 0.03 mmol), piperidine (0.05 mL), and pyridine (0.05
C NMR 158.5, 157.9, 133.7, 131.4, 130.9, 129.3, 129.0 (2 C),
C
128.2 (2 C), 127.3, 113.7, 113.1, 78.0, 64.6, 37.7, 36.0, 35.8,
35.2, 26.4, 20.8, 20.6, 17.8; IR (neat) 2926, 1651, 1537, 1232;
UV (MeOH) λmax nm (ꢀ) 287 (6 200, sh), 242 (23 900), 201
(26 900); (MeOH + HCl) 295 (3 000, sh), 242 (23 000), 200
(27 000); (MeOH + NaOH) 295 (3 000, sh), 242 (23 000), 213
(
2
1
13
(
(62 700). The H NMR and C NMR spectral data in CDCl
3
are identical to those of natural (-)-leporin A.1 Natural and
synthetic leporin A are also identical by TLC (4:1 hexane:
EtOAc) comparison.
H
25NO
2
7
(
4-Br om obu tyl tetr a h yd r op yr a n yl eth er (25) was pre-
pared from dihydropyran (3.9 mL, 42.3 mmol), alcohol 24 (6.0
g, 39.2 mmol), and p-TsOH (11 mg), as described above for
the preparation of 19, giving 6.5 g (70%) of 25: 1H NMR 4.59-
mL) in absolute EtOH (0.5 mL) was heated at 100 °C for 12 h.
Removal of the solvent under reduced pressure followed by
flash chromatography of the residue on silica gel (3:4 hexane-
EtOAc) gave 6.5 mg (65%) of 22 as a white, waxy solid followed
4.56 (m, 1), 3.89-3.73 (m, 2), 3.54-3.39 (m, 2), 3.46 (t, 2, J )
1
13
by 2 mg (20%) of recovered 21: mp 75-76 °C; H NMR 8.47
6.8), 2.03-2.0 (m, 2), 1.99-1.70 (m, 4), 1.68-1.48 (m, 4);
C
(br s, 1, NH), 7.37-7.27 (m, 5), 7.36 (s, 1), 5.77 (ddd, 1, J )
NMR 98.8, 66.4, 62.3, 33.6, 30.6, 29.8, 28.3, 25.4, 19.6; IR (neat)
2942, 2870, 1440, 1201.
9
1
1
1
6
3
.4, 2.5, 2.5), 5.46 (ddd, J ) 9.4, 3.1, 3.1), 2.77 (m, 1), 2.44 (m,
), 2.02 (dd, 1, J ) 10.5, 10.5), 1.98 (m, 1), 1.92-0.90 (m, 6),
.04 (d, 3, J ) 7.3), 0.69 (d, 3, J ) 6.6); 13C NMR 196.5, 177.3,
38.3, 135.9, 133.5, 128.4 (2 C), 128.3 (2 C), 128.2, 127.7, 119.8,
4.6, 52.8, 41.8, 38.7, 36.5, 34.4, 33.6, 25.7, 21.7, 18.1; IR (neat)
260, 2923, 1699; UV (MeOH) λmax nm (ꢀ) 324 (7 400), 240
6E,8E-Deca d ien -1-ol (26) was prepared from magnesium
(262 mg, 10.7 mmol), bromide 25 (1.9 g, 8.0 mmol), 2E,4E-
hexadien-1-yl acetate (448 mg, 3.2 mmol) and Li CuCl (1.28
2 4
mL, 0.1 M in THF) in THF (15 mL), as described for the
preparation of 20, giving 307 mg (25%) of 26 after hydrolysis
1
(14 000); (MeOH + HCl) 324 (7 400), 240 (14 000); (MeOH +
of the THP ether: H NMR 6.00-5.95 (m, 2), 5.63-5.49 (m,
NaOH) 385 (7 000), 270 (10 500).
2), 3.63 (t, 2, J ) 6.6), 2.07 (td, 2, J ) 6.8, 6.8), 1.72 (d, 3, J )
6.3), 1.57 (tt, 2, J ) 7.0, 7.0), 1.43-1.32 (m, 4); 13C NMR 131.7,
131.6, 130.4, 126.8, 62.9, 32.6, 32.4, 29.2, 25.2, 18.0; IR (neat)
3350, 2933, 2860, 1457.
A solution of 21 in absolute EtOH (1 mL) was heated at
1
00 °C for 12 h. About 30% conversion to 22 was obtained
based on analysis of the NMR spectrum.
A solution of 3 (10 mg, 0.03 mmol), piperidine (0.05 mL),
and pyridine (0.05 mL) in absolute EtOH (0.5 mL) was heated
6E,8E-Deca d ien a l (27) was prepared from alcohol 26 (276
mg, 1.8 mmol), as described above for the preparation of 6,

2
844 J . Org. Chem., Vol. 61, No. 8, 1996
Snider and Lu
providing 251 mg (92%) of dienal 27 as a colorless oil: 1H NMR
(dddddd, 1, J ) 10.1, 10, 4, 2.3, 1, 1), 2.62 (dddq, 1, J ) 4.6, 1,
1, 6.7), 2.55 (d, 1, J ) 14.4), 2.39 (dd, 1, J ) 14.4, 3.0), 2.37
(dd, 1, J ) 14.4, 3.0), 1.82-1.72 (m, 4), 1.61-1.57 (m, 1), 1.4
(br dd, 1, J ) 10, 10), 1.28-0.98 (m, 3), 1.12 (s, 3), 0.88 (d, 3,
J ) 6.7), 0.85 (s, 3); 13C NMR 208.7, 208.3, 132.4, 126.3, 69.0,
53.2, 52.6, 39.0, 37.9, 37.1, 34.3, 30.7, 30.1, 27.6, 27.4, 27.1,
26.2, 18.8; IR (neat) 2930, 2852, 1723, 1693.
9
.76 (t, 1, J ) 1.7), 6.00-5.95 (m, 2), 5.64-5.47 (m, 2), 2.42
(td, 2, J ) 7.3, 1.7), 2.08 (td, 2, J ) 7.2, 7.2), 1.72 (d, 3, J )
1
3
6
2
.4), 1.64 (tt, 2, J ) 7.6, 7.3), 1.42 (tt, 2, J ) 7.6, 7.2); C NMR
02.6, 131.5, 131.0, 130.8, 127.2, 43.7, 32.2, 28.8, 21.6, 18.0;
IR (neat) 2935, 2851, 1722, 1457.
Con d en sa tion of Dien a l 27 a n d 5,5-Dim eth ylcycloh ex-
a n e-1,3-d ion e (28). A solution of dienal 27 (41.2 mg, 0.26
mmol), dione 28 (41.7 mg, 0.23 mmol), and ethylenediammo-
Partial data for 32: 1H NMR 5.68 (ddd, 1, J ) 9.8, 3.7, 2.2),
5.31 (br d, 1, J ) 9.8).
nium diacetate (0.4 mg) in CH
2 2
Cl (4 mL) was stirred at rt for
1
2 h. The solvent was removed under reduced pressure. The
Ack n ow led gm en t. We are grateful to the National
Institutes of Health for financial support. We thank
Prof. J ames Gloer, University of Iowa, for a sample of
natural leporin A, Prof. Thomas Pochapsky and Mr.
Huaping Mo for carrying out 2D NMR studies on
compound 22, and Mr. Hemant Khanna for developing
the synthesis of 5.
combined residue (134 mg) from two reactions (a total of 65
mg of dienal 27) was purified by flash chromatography on silica
gel (6:1 hexane-EtOAc), giving 47 mg (40%) of a 1:1 mixture
of 31 and 32 as a colorless oil, followed by 36 mg (21%) of 31
as a white solid, followed by 9 mg (5%) of 30 as a colorless oil.
1
Data for 30: H NMR 5.79 (dq, 1, J ) 15.2, 6.4), 5.45 (ddq,
1
, J ) 15.2, 8.7, 1.6), 3.94 (dd, 1, J ) 10.0, 8.7), 2.87 (br d, 1,
J ) 12.8), 2.24 (br s, 2), 2.22 (d, 1, J ) 16.4), 2.16 (d, 1, J )
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
1
1
6.4), 2.14-2.04 (m, 1), 1.84-1.66 (m, 2), 1.72 (dd, 3, J ) 6.4,
.6), 1.44-1.22 (m, 4), 1.06 (s, 3), 1.04 (s, 3), 1.02-0.67 (m, 2);
C NMR 187.9, 169.4, 132.0, 128.4, 113.9, 82.7, 51.5, 44.4,
2.8, 37.8, 31.4, 30.0, 29.4, 28.3, 27.2, 26.4, 26.0, 17.9; IR (neat)
930, 2860, 1651, 1611.
spectra of compounds 1-3, 6, 20-22 (14 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
1
3
4
2
1
Data for 31: mp 70-74 °C; H NMR 5.48 (br d, 1, J ) 10.1),
5
.41 (ddd, 1, J ) 10.1, 4.6, 2.3), 2.89 (d, 1, J ) 14.4), 2.70
J O952053I