Formal synthesis of (±)-isodihydronepetalactone

Article abstract of DOI:10.1002/jccs.200200036

A formal synthesis of (±)-isodihydronepetalactone (1) from cyclobutenone 5 was described. Baeyer-Villiger lactonization of cyclobutanone 8 followed by decholorination led to lactone 4, which underwent a series of functional group transformations, furnishe

Full text of DOI:10.1002/jccs.200200036

JournaloftheChineseChemicalSociety, 2002, 49, 233-237
233
FormalSynthesisof(±)-Isodihydronepetalactone
Meng-Yang Changa (
), Bo-Rui Changb (
), Chung-Ho Changa (
),
Shui-Tein Chena* (
) and Nein-Chen Changb* (
)
aInstituteofBiologicalChemistry,AcademiaSinica,Nankang,Taipei115,Taiwan,R.O.C.
bDepartmentofChemistry,NationalSunYat-SenUniversity,Kaohsiung804,Taiwan,R.O.C.
A for mal syn the sis of (±)-isodihydronepetalactone (1) from cyclobutenone 5 was de scribed. Baeyer-
Villiger lactonization of cyclobutanone8 fol lowed by decholorination led to lactone 4, whichunderwentase-
ries of func tional group trans for ma tions, fur nished cyclopentanone de riv a tive 15. Shapiro reactionon
hydrazone de riv a tive in the pres ence of ex cess dry ice gave lactone 2. Lactone 2 had pre vi ously been con-
verted to isodihydronepetalactone ( 1).
INTRODUCTION
RESULTS AND DISCUSSION
The iridoids com prise a large fam ily of monoterpenoid
characterizedbyacyclopentaneringcis-fused to a dihydro-
pyran ord-lactone. 1-3 These iridoid monoterpenoid have con-
tig u ous chiral cen ters on their mo lec u lar sys tem and pro-
nouncedphysiologicalactivities.4-6 Strat egies adopted for the
syn the sis of isodihydronepetalactone (1) have at tracted the
attentionofsyntheticchemists.7-12 Isodihydronepetalactone
(1) was iso lated by Sakan and his co-workers from Actinidia
polygamaMiq..ItsbiologicalactivitiestowardFelidae an i-
mals and in sec ti cidal prop er ties are the fo cal points of the
syntheticchemists.4,6,13 We now wish to re port a new ap-
proach to the syn the sis of iridoid monoterpene lactone 2.7-9,18
The readily avail able cyclobutenone 5 was used as start ing
ma te rial. Retrosynthesis of isodihydronepetalactone (1) is
shown in Scheme I. The trans for ma tion of lactone ring from
bicyclo[3.3.0]heptanone 4 to bicyclo[4.3.0]octenone 2 was a
key point. The Shapiro re ac tion played an im por tant role and
pro vided a car bon moi ety by car bon di ox ide in the for mal
synthesis.
As shown in Scheme II, our synthesis started with
cyclobutenonederivative 5, which was eas ily ob tained on a
mole scale from freshly pre pared cyclopentadiene. The cy-
clo addition step pro ceeded well by re ac tion of cyclo pen-
tadiene, in situ generation of methyl chloroketene from
triethylamine and a -chloropropionyl chlo ride to pro duce the
cycloadduct 5 as a ma jor prod uct.19-21 Baeyer-Villiger lacto-
nization of ketone 5 with m-chloroperoxybenzoic acid
(MCPBA) in ba sic con di tion gave lactone 6 in 59% yield.21
Lactone 6 was reduced with lithium aluminum hydride
(LAH) to give diol 7 as a ma jor prod uct in low yield. To pre-
ventpooryieldandcomplexresults,theunsaturatedketone5
was hy dro ge nated to ketone 8. How ever, when a - chloro-
ketone 8 was sub jected to dechlorination by re ac tion of zinc
powderinaceticacidatroomtemperature,thesingleproduct
9 was af forded.20,22 Baeyer-Villiger lactonization of ketone 9
with MCPBA fur nished 2:1 mix ture of lactone 10 and 11, but
the regioselectivity was frequently lack ing. On the other
hand, when we change the se quence of dechlorination and
lactonization, a -chlorocyclobutanone 8undercomparable
conditionsunderwentexclusivemigrationofthenon-chlo-
rinated car bon as the only prod uct 12.21 Dechlorination was
com pleted af ter 40 h at room tem per a ture and it pro duced a
sin gle com pound4. The struc tural as sign ment of lactone 4
Scheme I
O
O
O
CH3
O
O
O
1
and 11 was based on its H NMR spec tral as re ported in the
O
literature.23-24 Protonation of the enol form of lactone 4 from
the endo face was af fected by the ox y gen of lactone 4. The
ox y gen could pro duce hy dro gen bond ing with a pro ton of
ace tic acid to epimerize the methyl group from endo face to
exoface. The in ter est ing dechlorination pro cess pro vided
com pound4 in 84% yield. Re duc tion of lactone 4 with LAH,
fol lowed by acetylation of the re sult ing diol, gave the mono-
CH3
isodihydronepetalactone (1)
CH3
CH3
2
3
O
O
O
CH3
Cl
CH3
4
5

234 J. Chin. Chem. Soc., Vol. 49, No. 2, 2002
Chang et al.
acetylatedalcohol14 asamajorproduct. Inordertoincrease
the yield, the diacetylated prod uct 13 was trans formed back
todiolinbasicconditions.7 Withalcohol14in hand, the al co-
hol 14 was ox i dized with pyridinium chlorochromate (PCC)
togivethecorrespondingketone15.Condensationofketone
15 with 4-toluenesulfonylhydrazine (TsNHNH2) af forded
hydrazone de riv a tive in nearly quan ti ta tive yield. Finally,
conversionofthehydrazonederivativetocyclopentapyra-
none 2 was ac com plished via Shapiro re ac tion.7 Dianion 3
wasproducedwithexcessn-butyllithium from hydrazone de-
riv a tive and it re acted with car bon di ox ide to give hydroxy-
acidcompound.Withoutpurification,cyclizationofhydroxy-
acidprovidedthelactone2 inacidicconditions. Thelactone2
was iden ti cal to those re ported by Pro fes sor Uyehara and
Yamamoto.25 The above pro ce dure con sti tutes a new ap-
proachtotheformalsynthesisofisodihydronepetalactone( 1)
via a com bi na tion of [2+2] cycloaddition and Shapiro re ac-
tion.
reagents and solvents were obtained from commercial
sourcesandusedwithoutfurtherpurification.Reactionswere
rou tinely car ried out un der an at mo sphere of dry ni tro gen
with mag netic stir ring. The ex tracted so lu tion with prod ucts
was dried with an hy drous MgSO4 beforeconcentrationin
vacuo. All re ported tem per a tures are un cor rected. Crude
productswerepurifiedbycolumnchromatographyonsilica
gel.
7-Chloro-7-methylbicyclo[3.2.0]hept-2-en-6-one (5)
To a stirred so lu tion of cyclopentadiene (10.0 g, 151.5
mmol)andtriethyamine(10.7g, 105.7mmol)incyclohexane
(300 mL) was added a -chloropropinoyl chlo ride (9.6 g, 75.6
mmol)atroomtemperature.After3h,theprecipitatewasre-
moved by filtration, and the solvent was concentratedin
vacuo.Theresiduewaspurifiedbycolumnchromatography
with sil ica gel (hex ane/ethyl ac e tate = 30/1) to pro vide a c.a.
4:1 ra tio of cycloadduct 5 (7.7 g, 65%) and its epimer (1.9 g,
16%) as col or less oils. For chloroketone 5: 1H NMR (300
MHz, CDCl3) d 6.00-5.96 (m, 1H), 5.77-5.72 (m, 1H), 4.31-
4.24 (m, 1H), 3.72-3.68 (m, 1H), 2.73-2.66 (m, 1H), 2.52-
2.42 (m, 1H), 1.49 (s, 3H); 13C NMR (75 MHz, CDCl3) d
207.7, 136.2, 128.4, 79.1, 59.6, 55.0, 34.1, 18.8; HRMS calcd
for C8H9OCl 156.0343, found 156.0340.
Scheme II
O
OH
O
(b) (39%)
(a) (59%)
OH
O
CH3
CH3
CH3
Cl
Cl
Cl
O
5
6
7
3-Chloro-3-methyl-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]-
oxol-2-one (6)
(c) (97%)
O
O
O
CH3
(a) (88%)
(d) (84%)
A solution of chloroketone 5 (2.0 g, 12.8 mmol) in
meth y lene chlo ride (40 mL) was added dropwise at room
temperaturetoasolutionofsodiumbicarbonate(NaHCO3)
(3.0 g) and MCPBA (2.8 g, 16.2 mmol) in meth y lene chlo ride
(30mL).Theresultingmixturewasstirredatthistemperature
for 6 h. The pre cip i tate was fil tered off, and the fil trate was
washedwithaqueoussaturatedsodiumbicarbonatesolution.
The or ganic layer was washed with brine, dried (MgSO4), and
concentratedtogivecrudelactone6.Chromatographyonsil-
ica gel (hex ane/ethyl ac e tate = 4/1) af forded lactone 6 as a
col or less oil (1.3 g, 59%): IR (CHCl3, cm-1) 1735; 1H NMR
(300 MHz, CDCl3) d 5.96-5.92 (m, 1H), 5.61-5.59 (m, 1H),
5.27-5.24 (m, 1H), 3.75-3.72 (m, 1H), 2.78-2.56 (m, 2H),
1.81 (s, 3H); 13C NMR (75 MHz, CDCl3) d 173.3, 132.8,
126.0, 80.5, 64.3, 61.1, 38.6, 22.9; HRMS calcd for C8H9O2Cl
172.0292, found 172.0294.
10
+
CH3
Cl
(10/11=2/1)
O
CH3
O
8
9
(c) (97%) then (a) (88%)
(two steps from 5)
CH3
OAc
11
O
O
(b) (88%)
(e) (85%)
(d) (84%)
O
O
OAc
CH3
Cl
12
CH3 (13/14=1/7.5)
CH3
OH
4
13
O
+
O
(g), (h)
(60%)
(f) (87%)
O
OAc
OAc
CH3
CH3
CH3
15
14
2
(a) MCPBA, NaHCO3, CH2Cl2, rt; (b) LAH, THF, rt; (c) H2, Pt/C, EtOAc, rt;
(d) Zn, AcOH, rt; (e) Ac2O, Pyr., CH2Cl2, 0 oC; (f) PCC, Celite, CH2Cl2, rt;
(g) TsNHNH2, THF, rt; (h) n-BuLi, CO2(g), -78 oC, then 2N HCl
EXPERIMENT SECTION
2-Chloro-2-(5-hydroxy-2-cyclopentenyl)-1-propanol (7)
To a so lu tion of LAH (210 mg, 5.8 mmol) in THF (40
mL) was added a so lu tion of lactone 6 (1.0 g, 5.8 mmol) in
THF (10 mL) via sy ringe at 0 °C. The mix ture was refluxed
for2h,quenchedwithsaturatedaqueousammoniumchloride
General
Tetrahydrofuran (THF) was dis tilled prior to use from a
deep-blue so lu tion of so dium-benzophenone ketyl. All other

For mal Syn the sis of (±)-Isodihydronepetalactone
J. Chin. Chem. Soc., Vol. 49, No. 2, 2002 235
solution(NH4Cl) (2 mL) un der cool ing, and con cen trated.
The res i due was di luted with wa ter (15 mL) and ex tracted
withethylacetate(3´ 30 mL). The or ganic layer was washed
with brine and wa ter, dried (MgSO4), fil tered and con cen-
trated to af ford crude diol 7. Chromatographyonsilicagel
(hexane/ethylacetate=3/1)affordeddiol7 (0.4 g, 39%) as a
col or less oil: IR (CHCl3, cm-1) 3455; 1H NMR (300 MHz,
CDCl3) d 5.96-5.91 (m, 1H), 5.84-5.82 (m, 1H), 4.60 (td, J =
5.7, 2.1 Hz, 1H), 3.97 (d, J = 11.7 Hz, 1H), 3.80 (d, J = 11.7
Hz, 1H), 3.15-3.12 (m, 1H), 2.69-2.60 (m, 1H), 2.42-2.34 (m,
1H), 2.35 (brs, 2H), 1.73 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 130.4, 129.5, 76.9, 73.6, 70.4, 58.4, 42.6, 25.6; HRMS
calcd for [M+-H2O] C8H11OCl 158.0499, found 158.0502.
2.90-2.76 (m, 2H), 2.05-1.83 (m, 2H), 1.74-1.54 (m, 4H),
1.21 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 179.4,
84.2, 43.9, 38.0, 32.7, 25.7, 24.1, 11.1; HRMS calcd for
C8H12O2 140.0837, found 140.0837.
3-Chloro-3-methylhexahydrocyclopenta[b]furan-2-one
(12)
A solution of chloroketone 8 (5.0 g, 31.5 mmol) in
meth y lene chlo ride (40 mL) was added dropwise at room
tem per a ture to a so lu tion of MCPBA (7.6 g, 44.1 mmol) and
NaHCO3 (8.0 g) in meth y lene chlo ride (60 mL), and the re-
sult ing mix ture was stirred at this tem per a ture for 4 h. The
pre cip i tate was fil tered off, and the fil trate was washed with
aqueoussaturatedNaHCO3 so lu tion. The or ganic layer was
washed with brine, dried (MgSO4), and con cen trated to give
crude lactone 12.Chromatography on sil ica gel (hex ane/
ethylacetate=4/1)affordedlactone12 as a col or less oil (4.8
g, 88%): IR (CHCl3, cm-1) 1740; 1H NMR (300 MHz, CDCl3)
d 5.13 (dt,J = 5.1, 2.1 Hz, 1H), 2.98 (td, J = 8.4, 5.1 Hz, 1H),
2.10-1.40 (m, 6H), 1.76 (s, 3H);13C NMR (75 MHz, CDCl3) d
173.8, 84.4, 66.3, 55.0, 31.3, 27.2, 24.6, 22.2; HRMS calcd
for C8H11O2Cl 174.0448, found 174.0441.
endo-3-Methyl-hexahydro-cyclopenta[c]furan-1-one (10)
and endo-3-Methyl-hexahydro-cyclopenta[b]furan-2-one
(11)
Asolutionofunsaturatedketone 5 (5.0 g, 32.0 mmol) in
ethyl ac e tate (50 mL) was stirred un der 1 atm of hy dro gen at
room tem per a ture with 10% plat i num on char coal (100 mg)
for2h.Themixturesolutionwasfiltered,andthefiltratewas
evap o rated to give crude sat u rated ketone 8 (4.9 g, 97%).
Withoutpurification,asuspensionofchlorolactone8 (4.9 g,
30.9 mmol) and zinc pow der (6.5 g, 100.0 mmol) in ace tic
acid (20 mL) was stirred at room tem per a ture for 4 h. Meth y-
lene chlo ride (50 mL) was added to the re ac tion mix ture, and
theexcesszincpowderwasfilteredoff.Theorganicsolution
wasalkalizedwithanaqueoussolutionofsaturatedsodium
bicarbonate(NaHCO3) at 0°C, and the or ganic layer was sep-
arated. The organic layer was washed with brine, dried
(MgSO4), and con cen trated to give crude lactone 9 (3.2 g,
84%).Withoutpurification,asolutionofchloroketone9 (3.2
g, 25.8 mmol) in meth y lene chlo ride (30 mL) was added
dropwiseatroomtemperaturetoasolutionofMCPBA(6.6g,
38.3 mmol) and NaHCO3 (6.0 g) in meth y lene chlo ride (50
mL),andtheresultingmixturewasstirredatthistemperature
for 4 h. The pre cip i tate was fil tered off, and the fil trate was
washed with aque ous sat u rated NaHCO3 so lu tion. The or-
ganic layer was washed with brine, dried (MgSO4), and con-
centratedtogivecrudeproducts. Chromatographyonsilica
gel (hex ane/ethyl ac e tate = 10/1) af forded to pro vide a c.a.
2:1 ra tio of lactone 10 (2.1 g, 58%) and its iso mer 11 (1.08 g,
30%) as the col or less oils: For10: IR (CHCl3, cm-1) 1746; 1H
NMR (300 MHz, CDCl3) d 4.77-4.68 (m, 1H), 3.12 (td, J =
8.4, 3.9 Hz, 1H), 2.82-2.72 (m, 1H), 2.07-1.93 (m, 2H),
1.76-1.54 (m, 4H), 1.37 (d, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) d 180.6, 77.0, 46.9, 44.5, 29.1, 26.2, 26.1, 16.4;
HRMS calcd for C8H12O2 140.0837, found 140.0841. For11 :
1H NMR (300 MHz, CDCl3) d 4.86 (dt, J = 5.4, 1.7 Hz, 1H),
exo-3-Methylhexahydrocyclopenta[b]furan-2-one (4)
A sus pen sion of chlorolactone 12 (4.0 g, 23.0 mmol)
and zinc pow der (7.5 g, 115.0 mmol) in ace tic acid (20 mL)
wasstirredatroomtemperaturefor40h.Methylenechloride
(50 mL) was added to the re ac tion mix ture, and the ex cess
zinc pow der was fil tered off. The or ganic so lu tion was al ka-
lizedwithanaqueoussolutionofsaturatedNaHCO3 at 0 °C,
and the or ganic layer was sep a rated. The or ganic layer was
washed with brine, dried (MgSO4), and con cen trated to give
crude lactone 4.Chromatographyonsilicagel(hexane/ethyl
ac e tate = 10/1) af forded lactone 4 as a col or less oil (2.7 g,
84%): 1H and13C NMR data was the same as for ref er ence 23.
HRMS calcd for C8H12O2 140.0837, found 140.0833.
2-(2-Hydroxycyclopentyl)propyl acetate(14)
To a so lu tion of LAH (0.6 g, 16.0 mmol) in THF (40
mL) was added a so lu tion of lactone 4 (2.0 g, 14.3 mmol) in
THF (10 mL) via sy ringe at 0 °C. The mix ture was refluxed
for 2 h, quenched with sat u rated aque ous NH4Cl so lu tion (2
mL) un der cool ing, and con cen trated. The res i due was di-
lutedwithwater(15mL)andextractedwithethylacetate(3´
30 mL). The or ganic layer was washed with brine and wa ter,
dried (MgSO4),filteredandconcentratedtoaffordcrudediol
(1.8g,88%).Withoutpurification,theaceticanhydride(1.3
g, 12.7 mmol) was added dropwise to a cold (0 °C), magneti-
cally stirred so lu tion of diol (1.8 g, 12.5 mmol) in pyridine

236 J. Chin. Chem. Soc., Vol. 49, No. 2, 2002
Chang et al.
(10 mL). Af ter be ing al lowed to warm at room tem per a ture,
the mix ture was stirred for 2 h. Then wa ter (10 mL) was
added to the mix ture and ex tracted with ethyl ac e tate (3 ´ 30
mL). The or ganic layer was washed with brine and wa ter,
dried (MgSO4), fil tered and con cen trated to af ford crude
products.Chromatographyonsilicagel(hexane/ethylacetate
= 5/1) af forded diacetate 13 (280 mg, 10%) and monoacetate
14 (1.74 g, 75%) as colorless oils. For diacetate 13: IR
(CHCl3, cm-1) 1728; 1H NMR (300 MHz, CDCl3) d 5.19 (t, J
= 4.2 Hz, 1H), 4.04 (dd, J = 10.8, 5.1 Hz, 1H), 3.84 (dd, J =
10.8, 6.3 Hz, 1H), 2.04 (s, 6H), 1.98-1.46 (m, 8H), 0.97 (d,J =
6.6 Hz, 3H);13C NMR (75 MHz, CDCl3) d 171.1, 170.7, 76.7,
68.7, 47.8, 33.0, 32.3, 28.3, 21.5, 21.3, 21.0, 16.5. For
monoacetate 14: IR (CHCl3, cm-1) 1732, 3450; 1H NMR (300
MHz, CDCl3) d 4.25-4.23 (m, 1H), 4.12 (dd, J = 10.8, 3.9 Hz,
1H), 3.90 (dd, J = 10.8, 6.9 Hz, 1H), 2.06 (s, 3H), 1.95-1.40
(m, 9H), 1.07 (d,J = 6.9 Hz, 3H);13C NMR (75 MHz, CDCl3)
d 171.3, 73.7, 69.0, 49.0, 34.8, 33.0, 26.8, 21.8, 20.9, 16.6;
HRMS calcd for C10H18O3 186.1256, found 186.1260.
reactionwasaddedanexcessofdryice(carbondioxide)and
the so lu tion was stirred at -78 °C for 1 h. The re ac tion was
quenchedwith2Naqueoushydrogenchloride(3mL)atroom
temperaturefor1h.Thesolventwasremovedunderreduced
pres sure and its res i due was taken up with wa ter (10 mL) and
ex tracted with ethyl ac e tate (3´ 30 mL). The or ganic layer
was washed with brine, dried (MgSO4), fil tered and con cen-
trated to af ford crude 2. Chro ma tog ra phy on sil ica gel (hex-
ane/ethyl ac e tate = 10/1) af forded 2 (260 mg, 60%) of as a
1
col or less oil: IR (CHCl3) 1744 cm-1; H NMR (300 MHz,
CDCl3) d 7.00 (dd,J = 2.7, 2.4 Hz, 1H), 4.29 (dd, J= 11.7, 4.5
Hz, 1H), 3.94 (dd, J = 11.7, 11.7 Hz, 1H), 2.70-2.30 (m, 3H),
1.75-1.70 (m, 1H), 1.60-1.50 (m, 2H), 0.97 (d, J = 6.3 Hz,
3H); 13C NMR (CDCl3, 75 MHz) d 163.4, 145.7, 134.0, 75.2,
48.9, 36.2, 31.8, 31.1, 14.3; MS (30 eV) m/z 152 (M+, 40),
122 (40), 93 (85), 79 (100); HRMS calcd C9H12O2 152.0838,
found 152.0838.
ACKNOWLEDGMENT
2-(2-Oxo-cyclopentyl)propyl ac e tate (15)
Thealcohol13 (1.5g,8.1mmol)inmethylenechloride
(10 mL) was added to a mix ture of PCC (2.3 g, 10.7 mmol)
andCelite(5.0g)inmethylenechloride(50mL).Afterbeing
stirred at room tem per a ture for 2 h, the mix ture was di luted
with ethyl ac e tate (20 mL) and fil tered through a short sil ica
gel col umn. The fil trate was washed with wa ter (2 ´ 10 mL),
dried (MgSO4), fil tered and con cen trated to pro duce crude
ketone 15.Chromatographyonsilicagel(hexane/ethylace-
tate = 4:1) af forded ketone 15 (1.33 g, 90%) as a col or less oil:
The au thors would like to thank the Na tional Sci ence
CounciloftheRepublicofChinaforfinancialsupport.
Received October 17, 2001.
Key Words
Isodihydronepetalactone; Monoterpenoid; [2+2]
Cycloaddition; Shapiro reaction.
1
IR (CHCl3, cm -1 ) 1729; H NMR (300 MHz, CDCl3) d 4.10-
3.90 (m, 2H), 2.50-2.20 (m, 3H), 2.10-2.00 (m, 3H), 2.06 (s,
3H), 1.78-1.60 (m, 2H), 0.82 (d, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 220.0, 170.9, 67.6, 50.7, 38.7, 31.5, 24.1,
20.9, 20.6, 12.7; HRMS calcd for C10H16O3 184.1100, found
184.1103.
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p-Toluenesulfonylhydrazine (1.0 g, 5.9 mmol) and
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For mal Syn the sis of (±)-Isodihydronepetalactone
J. Chin. Chem. Soc., Vol. 49, No. 2, 2002 237
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25. We thank Pro fes sor Tadao Uyehara, Uni ver sity of Utsunomiya
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