Convergent synthesis of pancratistatin from piperonal and xylose

Article abstract of DOI:10.1002/ejoc.200900719

A synthesis of the antitumour agent pancratistatin is described from piperonal and D-xylose. Piperonal is converted into cinnamyl bromide 11 while methyl 5-iodoribofuranoside 12 is derived from xylose, The allylic bromide and the iodocarbohydrate are combined in a zinc-mediated tandem reaction to afford a highly functionalised 1,7-diene, which is then converted into the corresponding cyclohexene by ring-closing olefin metathesis. Subsequent Overman rearrangement, dihydroxylation and deprotection afford the natural product in a total of 25 steps from, the two starting materials. The longest linear sequence is from piperonal and gives rise to pancratistatin in 18 steps and 7.0% overall yield. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900719

FULL PAPER
DOI: 10.1002/ejoc.200900719
Convergent Synthesis of Pancratistatin from Piperonal and Xylose
Johan Hygum Dam[a] and Robert Madsen*[a]
Keywords: Allylation / Antitumour agents / Metathesis / Natural products / Total synthesis
A synthesis of the antitumour agent pancratistatin is de-
scribed from piperonal and -xylose. Piperonal is converted
into cinnamyl bromide 11 while methyl 5-iodoribofuranoside
12 is derived from xylose. The allylic bromide and the iodo-
carbohydrate are combined in a zinc-mediated tandem reac-
tion to afford a highly functionalised 1,7-diene, which is then
ing olefin metathesis. Subsequent Overman rearrangement,
D
dihydroxylation and deprotection afford the natural product
in a total of 25 steps from the two starting materials. The
longest linear sequence is from piperonal and gives rise to
pancratistatin in 18 steps and 7.0% overall yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
converted into the corresponding cyclohexene by ring-clos- Germany, 2009)
Introduction
Pancratistatin was isolated in 1984 from the bulbs of the
Hawaiian Amaryllidaceae plant Hymenocallis littoralis.[1,2]
The structure was elucidated by NMR spectroscopy and X-
ray crystallographic analysis and the natural product was
shown to possess a highly hydroxylated phenanthridone
skeleton with six contiguous stereocentres (Figure 1). Sub-
sequent biological studies revealed that pancratistatin ex-
hibited strong in vitro cancer cell growth inhibitory activity
Figure 1. Structure of pancratistatin.
Pancratistatin is only available in small quantities from
when tested against a panel of human tumour lines.[3] Sig- natural sources. The original isolation in 1984 afforded the
nificant antiviral[4] and antiparasitic[5] activity have also natural product in only 0.028% yield from the available ma-
been observed. The detailed mechanism of action is not terial.[1] Although, the target molecule has also been iden-
known, but it has been shown that pancratistatin acts in the tified in other Amaryllidaceae species[9] the limited supply
mitochondria of the cancerous cells and induces has been a serious drawback in the development of pancrat-
apoptosis.[6] The potent antitumour activity has stimulated istatin as an antitumour agent. As a result, a number of
efforts to develop pancratistatin into an anticancer drug. total syntheses have been developed starting from either an
Due to the poor solubility of the parent molecule these in- achiral starting material or a compound from the chiral
vestigations have employed prodrugs of the natural product pool.[10] The first synthesis in 1989 was a racemic synthesis
containing either a 7-O-phosphate or a 3,4-O-cyclic phos- in a total of 26 linear steps from pyrogallol.[11] Since then
phate.[7] Many derivatives of pancratistatin have also been a total of eight asymmetric syntheses have appeared where
prepared and tested for antitumour activity to identify the six are enantioselective syntheses starting from various cy-
minimum cytotoxic pharmacophore.[8] The conclusion from clohexene or aromatic starting materials while two start
these studies has been that the entire phenanthridone skel- from members of the chiral pool – the natural products
eton, the trans B,C ring junction and the hydroxy groups at narciclasine and pinitol.[12] The shortest syntheses from
position 2, 3, 4, and 7 are necessary to maintain high bio- commercial starting materials are based on a whole-cell bio-
logical activity.
oxidation of bromobenzene,[12g] a palladium-catalysed de-
symmetrisation of conduritol A,[12h] and a ring-opening of
a cyclic sulfate in pinitol.[12a] In these three cases the natural
product is obtained in a total of 13–20 linear steps and 2–
7% overall yield.
Over the past decade we have exploited the synthesis of
carbocyclic natural products from carbohydrates by the use
of a zinc-mediated tandem reaction and ring-closing olefin
[a] Department of Chemistry, Building 201, Technical University
of Denmark,
2800 Lyngby, Denmark
Fax: +45-4593-3968
E-mail: rm@kemi.dtu.dk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900719.
4666
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Convergent Synthesis of Pancratistatin from Piperonal and Xylose
metathesis.[13,14] Methyl ω-iodoglycosides are subjected to in 74% overall yield from piperonal. Other directing groups
zinc metal in the presence of allylic bromides. Under these were also investigated in the ortho metallations, but the cor-
conditions, the starting glycoside undergoes a reductive responding 1,3-dimethylimidazolidine and N-cyclohexyl-
fragmentation to furnish an unsaturated aldehyde, which is imine of piperonal both gave significantly lower yields than
then allylated in situ. The α,ω-diene thus obtained is sub- the diethyl amide. Treatment of 6 with Meerwein’s reagent
sequently converted into the corresponding carbocycle by following Keck’s procedure[23] resulted in loss of the silyl
ring-closing metathesis. We and others have used the combi- group and concomitant transformation into ester 7.[22] Sub-
nation of these organometallic reactions to prepare several sequent benzyl protection furnished benzyl ether 8. The al-
carbocyclic natural products from carbohydrates including lylic moiety was introduced by a Heck coupling with acrylic
the calystegines,[15] the gabosines,[16] cyclophellitol[17] and 7- acid followed by reduction to the allylic alcohol 10. The
deoxypancratistatin.[18]
Heck reaction was carried out under phosphane-free condi-
Herein, we describe an expedient and convergent synthe- tions[24] because the presence of triphenylphosphane was
sis of pancratistatin from piperonal and xylose where a zinc- found to give only moderate yields. Conversion into the al-
mediated tandem reaction and ring-closing metathesis serve lylic mesylate and substitution with bromide then gave the
as the key steps.
desired allylating agent 11. Reagent 11 is crystalline and
completely stable at room temperature for many months.
Results and Discussion
The synthesis employs the same overall strategy as used
in our earlier synthesis of the 7-deoxy congener. The amide
nitrogen will be installed by an Overman rearrangement
from allylic alcohol B that in turn will be prepared by ring-
closing metathesis from diene C (Figure 2). The latter will
be assembled by a zinc-mediated tandem reaction between
allylating agent D and ribofuranoside E. The synthesis of
E from xylose was investigated in our earlier work[18] while
the allylating agent has not been described before.
Scheme 1. Synthesis of allylating agent.
The carbohydrate coupling partner 12 was prepared from
-xylose in 7 steps and 42% overall yield following our pre-
viously developed protocol.[18] With both the allylating
agent and the iodofuranoside in hand the stage was now
set to investigate the zinc-mediated tandem reaction. The
reaction was carried out in a 3:1 THF/H2O mixture under
sonication at 40 °C. Treatment of furanoside 12 with zinc
under these conditions and adding 1.5 equiv. of bromide 11
by syringe pump at the same time gave the coupling product
Figure 2. Retrosynthesis.
Piperonal (1) is a cheap starting material for ring A and as a 1.1:1 mixture of two diastereomers, which could not be
is easily oxidized with sodium chlorite – hydrogen perox- separated by silica gel chromatography (Scheme 2). Con-
ide[19] to piperonylic acid (2) and further converted into the trary to our earlier observations[18] the products were reluc-
corresponding diethylamide 3 (Scheme 1). To introduce the tant to lactonise and the crude product was therefore
hydroxy functionality a directed ortho metallation[20] was treated with potassium carbonate in acetonitrile to com-
employed followed by quenching with trimethyl borate and plete the lactonisation. Again, the products could not be
oxidation with hydrogen peroxide.[12g,21] The resulting separated and consequently the following metathesis reac-
phenol 4 was TBS protected and then converted into 6[22] tion was carried out with Hoveyda–Grubbs 2nd generation
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catalyst 13[25] to give 67% isolated yield of two cyclohexenes chloroacetamide is achieved with potassium carbonate in
which could now be separated. The main diastereomer 14 refluxing methanol. For the 7-deoxy analogue the free
was obtained in 35% yield from 12 and had the correct amine reacts immediately with the ester moiety to form the
stereochemistry for the natural product. The other dia- lactam.[18] However, the 7-benzyloxy group seems to ham-
stereomer was shown by NMR to be the all cis-configured per the rotation around the C10a–C10b bond[12g] and fur-
isomer 15.
ther activation is necessary for the lactamisation to occur.
DCC was used in the first synthesis,[11] but in our hands it
was also necessary to add HOBt in order to obtain a good
yield of lactam 18. With our modifications partially pro-
tected pancratistatin 18 is prepared from 14 in 49% overall
yield over the four steps as compared to 25% yield in the
first synthesis.[11] Final debenzylation of 18 by hydro-
genolysis proceeded in near quantitative yield to give (+)-
pancratistatin with optical rotation and NMR spectro-
scopic data in agreement with literature values. Neverthe-
less, it should be noted that carbon 10b at δ = 39.4 ppm has
not been assigned previously in the 13C NMR of pancratis-
tatin since it appears under the [D6]DMSO signal.
Scheme 2. Tandem reaction and metathesis.
Several experiments were performed in order to improve
the ratio between 14 and 15. In fact, increasing the THF/
H2O ratio to 9:1 did result in a 5:1 ratio of 14 and 15, but
unfortunately the combined yield of the two cyclohexenes
was only 22% in this case. Slight improvements in the dia-
stereomeric ratio were also observed when THF was re-
placed with dioxane or when the allylation was performed
in a saturated aqueous ammonium chloride solution, but
again the isolated yields were rather low. In other applica-
tions of the tandem reaction we have been able to isolate
the intermediate aldehyde and use a different metal in the
allylation step.[15c,17] Although, the aldehyde from fragmen-
tation of 12 could be isolated, the ensuing allylation with
11 in the presence of indium or tin failed completely. Since
it seems impossible to improve the diastereoselectivity with-
out compromising the yield we decided to continue the syn-
thesis with the 35% isolated yield of 14 over the key steps.
Cyclohexene 14 is identical with an intermediate in the
first racemic synthesis of pancratistatin.[11] However, we
have modified the experimental conditions for some of the
final steps in order to improve the yields. First, allylic
alcohol 14 is converted into the corresponding imidate with
trichloroacetonitrile and DBU which gave a better conver-
sion than with sodium hydride as the base (Scheme 3).[11]
The Overman rearrangement has previously been achieved
at 100–105 °C for 1.2 h under high vacuum,[11] but in our
hands the imidate was completely stable under these condi-
Scheme 3. Synthesis of (+)-pancratistatin.
Although pancratistatin and 7-deoxypancratistatin dis-
play a range of biological activities we are not aware that
they have been tested as glycosidase inhibitors. Since we
have previously prepared several carbocyclic natural prod-
ucts that act as glucosidase inhibitors[15a,15c,17] we decided
also to test the two pancratistatins. Both were evaluated
against baker’s yeast α-glucosidase, almond β-glucosidase
and almond α-mannosidase.[26] Interestingly, 7-deoxy-
pancratistatin was a moderate inhibitor of β-glucosidase (Ki
= 2.8ϫ10–5 ) while the parent molecule showed no inhibi-
tion of the three enzymes.
Conclusions
In summary, we have developed a convergent synthesis
tions. Nevertheless, heating the allylic imidate to 135 °C for of the antitumour agent pancratistatin from piperonal and
21 h did bring about the rearrangement and afforded amide -xylose. The synthesis employs a total of 18 linear steps
16 in good yield. Dihydroxylation of the olefin proceeded from piperonal and affords the natural product in 7.0%
slowly, but otherwise uneventfully from the concave side of overall yield. From -xylose the total number of linear steps
the ring system to give diol 17. Deprotection of the tri- is 15 and the overall yield is 7.1%. The number of steps and
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Convergent Synthesis of Pancratistatin from Piperonal and Xylose
1:1); m.p. 65–66 °C (ref.[28] 62–65 °C). IR (KBr): ν = 2983, 2944,
˜
overall yields of the target molecule compare favourably
with some of the most efficient syntheses of pancratistatin
that have been achieved to date.
2903, 1610, 1465, 1438, 1291, 1241, 1036 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 6.88–6.78 (m, 3 H), 5.97 (s, 2 H), 3.37 (br.
s, 4 H), 1.16 (br. s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.6, 148.2, 147.4, 130.9, 120.4, 108.1, 107.3, 101.2, 43.2, 40.1,
13.8 ppm. C12H15NO3 (221.3): calcd. C 65.14, H 6.83, N 6.33;
found C 65.50, H 6.77, N 6.28.
Experimental Section
General: THF was distilled from Na/benzophenone under N2,
while DMF and CH2Cl2 were dried with 3- and 4-Å molecular
sieves, respectively. Solvents used for chromatography were of
HPLC grade. Zinc dust (8.0 g, 122 mmol) was activated by stirring
with 2  HCl (150 mL) for 10 min, filtered and washed successively
with H2O, MeOH and Et2O, and dried with a heatgun under high
vacuum for 10 min to leave a fine, light grey powder. Sonications
were carried out in a sonic bath containing 1% liquid detergent.
Thin-layer chromatography was performed on aluminium plates
coated with silica gel 60. Visualisation was done by UV or by
dipping into a solution of cerium(IV) sulfate (2.5 g) and ammo-
nium molybdate (6.25 g) in 10% sulfuric acid (250 mL) followed
by charring with a heatgun. Flash chromatography was performed
with silica gel 60 (35–70 µm). Optical rotations were measured on
a Perkin–Elmer 241 polarimeter while IR spectra were recorded
with a Bruker Alpha FT-IR spectrometer. NMR spectra were re-
corded with a Varian Mercury 300 or a Varian Unity Inova 500
instrument. Chemical shifts were measured relative to the signals
of residual CHCl3 (δ = 7.26 ppm)/CDCl3 (δ = 77.0 ppm) or DMSO
(δ = 2.50 ppm)/[D6]DMSO (δ = 39.4 ppm). High-resolution mass
spectra were recorded at the Department of Physics and Chemistry,
University of Southern Denmark.
N,N-Diethyl-4-hydroxy-1,3-benzodioxole-5-carboxamide (4): Amide
3 (40.0 g, 0.181 mol) was dissolved in THF (500 mL) followed by
addition of dry TMEDA (30.0 mL, 0.199 mol). The mixture was
cooled to –78 °C and sBuLi (140 mL, 1.42  in cyclohexane,
0.199 mol) was added dropwise over 2 h with the temperature not
exceeding –72 °C. The deep red solution was stirred for 1 h at
–78 °C after which time dry B(OMe)3 (24.3 mL, 0.217 mol) was
added and the solution was warmed to 0 °C in an ice-bath. Then
acetic acid (16.8 mL, 0.293 mol) was added followed by slow ad-
dition of 35% H2O2 (42 mL, 0.488 mol). The solution was stirred
overnight at ambient temperature and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (600 mL) and washed with 10%
aqueous Na2S2O3 (1 L). The aqueous phase was filtered through a
pad of Celite and extracted with additional CH2Cl2 (2ϫ400 mL).
The combined organic phases were dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by dry column
vacuum chromatography[29] (EtOAc/heptane, 1:4 Ǟ 1:3) to yield
40.5 g (94%) of phenol 4. Rf = 0.30 (EtOAc/heptane, 1:1); m.p. 59–
60.5 °C. IR (KBr): ν = 2983, 2657, 1639, 1583, 1503, 1457, 1075,
˜
1
1033, 801 cm–1. H NMR (300 MHz, CDCl3): δ = 10.06 (s, 1 H),
6.85 (d, J = 8.3 Hz, 1 H), 6.40 (d, J = 8.3 Hz, 1 H), 6.01 (s, 2 H),
3.51 (q, J = 7.1 Hz, 4 H), 1.26 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.1, 150.7, 143.6, 135.2, 121.6, 114.2,
101.9, 99.6, 42.3, 13.3 ppm. C12H15NO4 (237.3): calcd. C 60.75, H
6.37, N 5.90; found C 60.87, H 6.31, N 5.89. MS: m/z = 260.1 [M
+ Na]+.
Piperonylic Acid (2): A solution of NaClO2 (48.0 g, 0.425 mol) in
H2O (400 mL) was added dropwise over 30 min to a stirred solu-
tion of piperonal (45.04 g, 0.300 mol) in MeCN (300 mL) contain-
ing NaH2PO4 (9.6 g, 0.080 mol) in H2O (120 mL) and 35% H2O2
(30 mL). The temperature was kept below 15 °C by the use of an
ice-bath. After the addition the ice-bath was removed and the solu-
tion was stirred for another 2 h. More NaH2PO4 (2.4 g, 0.020 mol)
and 35% H2O2 (8.0 mL) were added along with a solution of Na-
ClO2 (12.1 g, 0.134 mol) in H2O (60 mL). After 1 h additional Na-
ClO2 (4.0 g, 0.044 mol) was added and the mixture was stirred for
2 h before it was quenched with Na2SO3 (3.0 g). Then 37% HCl
(20 mL) was added and the slurry was filtered. The phases were
separated and the aqueous phase was extracted twice with EtOAc
(400 mL + 200 mL). The combined organic phases were dried with
MgSO4, filtered and concentrated to give 50.0 g (quantitative) of a
white solid. Rf = 0.58 (EtOAc/heptane/AcOH, 1:1:0.02); m.p. 225–
N,N-Diethyl-4-(tert-butyldimethylsilyloxy)-1,3-benzodioxole-5-carb-
oxamide (5): Phenol 4 (10.0 g, 42.2 mmol) was dissolved in CH2Cl2
(210 mL) under Ar and imidazole (5.74 g, 84.3 mmol) was added
followed by TBSCl (7.04 g, 46.7 mmol). The mixture was stirred at
room temperature overnight and filtered through a pad of Celite,
which was washed with CH2Cl2 (30 mL). The filtrate was washed
with saturated aqueous NaHCO3 (100 mL), H2O (250 mL), dried
with MgSO4, filtered, and concentrated in vacuo. The yellow oil
was purified by dry column vacuum chromatography[29] (EtOAc/
heptane, 1:19 Ǟ 1:1) to yield 14.8 g (quantitative) of an oil, which
solidified on standing. Rf = 0.47 (EtOAc/heptane, 1:1); m.p. 65 °C.
227 °C (ref.[27] 229–231 °C). IR (KBr): ν = 2918, 2560, 1671, 1617,
IR (KBr): ν = 2928, 2856, 1638, 1617, 1479, 1280, 1249, 1073, 1035,
˜
˜
865, 838 cm–1 1H NMR (300 MHz, CDCl3): δ = 6.68 (d, J =
.
1452, 1298, 1260, 1113, 1036 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 12.77 (br. s, 1 H), 7.54 (dd, J = 1.7, 8.1 Hz, 1 H), 7.36
(d, J = 1.6 Hz, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 6.12 (s, 2 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 166.6, 151.1, 147.4, 124.9,
124.6, 108.8, 108.0, 101.9 ppm. C8H6O4 (166.1): calcd. C 57.84, H
3.64; found C 57.78, H 3.73.
8.0 Hz, 1 H), 6.50 (d, J = 8.0 Hz, 1 H), 5.97–5.88 (m, 2 H), 3.51
(m, 2 H), 3.34–3.03 (m, 2 H), 1.22 (t, J = 7.2 Hz, 3 H), 1.01 (t, J
= 7.1 Hz, 3 H), 0.94 (s, 9 H), 0.21 (s, 3 H), 0.18 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.4, 148.9, 136.8, 135.3, 125.5,
120.7, 102.5, 100.9, 42.9, 39.3, 25.6, 18.2, 14.0, 13.2, –4.5 ppm.
C18H29NO4Si (351.5): calcd. C 61.50, H 8.32, N 3.98; found C
61.69, H 8.20, N 4.11. HRMS: calcd. for C36H58N2O8Si2Na [2M
+ Na]+ m/z 725.3629; found m/z 725.3617.
N,N-Diethyl-1,3-benzodioxole-5-carboxamide (3): Piperonylic acid
(74.5 g, 0.446 mol) was suspended in SOCl2 (325 mL, 4.46 mol) and
the mixture was heated to reflux for 1.5 h. The solution was cooled
to room temperature and excess SOCl2 removed under reduced
pressure. CH2Cl2 (350 mL) was added to the residue and the flask
was placed in an ice-bath followed by dropwise addition of dieth-
ylamine (185.2 mL, 1.78 mol). The mixture was stirred under Ar
overnight and then washed with 2  HCl (3ϫ1 L). The organic
phase was dried with MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (EtOAc/heptane,
3:7 Ǟ 1:1) to yield 88.6 g (90%) of 3. Rf = 0.25 (EtOAc/heptane,
N,N-Diethyl-4-(tert-butyldimethylsilyloxy)-6-iodo-1,3-benzodioxole-
5-carboxamide (6): Amide 5 (10.0 g, 2.85 mmol) was dissolved in
THF (140 mL) under Ar and TMEDA (4.5 mL, 2.99 mmol) was
added. The solution was cooled to –78 °C and sBuLi (23.5 mL,
1.33  in cyclohexane, 31.3 mmol) was added dropwise over 15 min
with the temperature not exceeding –74 °C. The mixture was stirred
for 2 h at –78 °C at which point it had become yellow. Then I2
(8.67 g in 34 mL of THF, 34.1 mmol) was added dropwise with the
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J. H. Dam, R. Madsen
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temperature not exceeding –70 °C and the cooling bath was re-
moved. The solution was warmed to room temperature and then
poured into H2O (200 mL) and saturated aqueous Na2S2O3
(30 mL). The phases were separated and the aqueous layer ex-
tracted with EtOAc (3ϫ100 mL). The combined organic phases
were dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (EtOAc/heptane, 1:6)
to yield 12.0 g (88%). Rf = 0.47 (EtOAc/heptane, 3:7); m.p. 66–
(2.9 mL, 12.1 mmol), acrylic acid (0.50 mL 7.28 mmol), Bu4NI
(0.896 g, 2.43 mmol) and Pd(OAc)2 (11.0 mg, 49 µmol, 2 mol-%)
were added, successively. The solution was heated to 100 °C for
2.5 h and then poured into 1  HCl (100 mL) and EtOAc (100 mL).
The phases were separated and the aqueous phase extracted with
EtOAc (2ϫ100 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography (EtOAc/heptane/AcOH, 1:1:0.01) to
67 °C. IR (KBr): ν = 2932, 2860, 1624, 1465, 1410, 1287, 1266, yield 0.861 g (quantitative) of a white solid. Rf = 0.21 (EtOAc/hep-
˜
1
1094, 1037, 874, 841 cm–1. H NMR (300 MHz, CDCl3): δ = 6.92 tane/AcOH, 1:1:0.01); m.p. 185–187 °C. IR (KBr): ν = 3300–2700,
˜
(s, 1 H), 5.95 (d, J = 1.4 Hz, 1 H), 5.92 (d, J = 1.4 Hz, 1 H), 3.92–
3.78 (m, 1 H), 3.25–3.08 (m, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.11
(t, J = 7.2 Hz, 3 H), 0.93 (s, 9 H), 0.22 (s, 3 H), 0.18 (s, 3 H) ppm.
2675, 1731, 1680, 1628, 1602, 1480, 1430, 1381, 1290, 1265, 1217,
1088, 1034 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J =
15.8 Hz, 1 H), 7.43–7.29 (m, 5 H), 6.86 (s, 1 H), 6.26 (d, J =
13C NMR (75 MHz, CDCl3): δ = 167.4, 149.3, 137.5, 135.9, 130.5, 15.7 Hz, 1 H), 6.04 (s, 2 H), 5.25 (s, 2 H), 3.89 (s, 3 H) ppm. 13C
112.5, 101.4, 82.2, 43.0, 39.3, 25.5, 18.2, 13.8, 12.6, –4.2, –4.7 ppm.
NMR (75 MHz, CDCl3): δ = 171.6, 166.7, 150.5, 142.9, 139.4,
C18H28INO4Si (477.4): calcd. C 45.28, H 5.91, N 2.93; found C 138.7, 136.4, 128.3, 128.1, 127.8, 127.0, 123.7, 118.4, 102.0, 100.7,
45.46, H 5.87, N 2.84. MS: m/z = 977.2 [2M + Na]+. NMR spectro-
74.2, 52.6 ppm. C19H16O7 (356.3): calcd. C 64.04, H 4.53; found C
63.83, H 4.62. HRMS: calcd. for C19H17O7 [M + H]+ m/z 357.0974;
found m/z 357.0980.
scopic data are in accordance with literature values.[22]
Methyl 4-Hydroxy-6-iodo-1,3-benzodioxole-5-carboxylate (7):
Amide 6 (12.30 g, 25.8 mmol) was dissolved in CH3CN (129 mL)
under N2 and Na2HPO4 (5.49 g, 38.7 mmol) and Me3OBF4
(11.44 g, 77.3 mmol) were added. The suspension was stirred for
3.5 h followed by slow addition of saturated aqueous NaHCO3
(161 mL) from an addition funnel under vigorous stirring. Ad-
ditional solid NaHCO3 (10.82 g, 128.8 mmol) was added and the
slurry was stirred at ambient temperature for 15 h, and then poured
into H2O (500 mL) and extracted with EtOAc (3ϫ200 mL). The
combined organic phases were dried with MgSO4, filtered, and
concentrated in vacuo. The residue was dissolved in CH2Cl2
(100 mL) and passed through a short column of silica to yield
7.867 g (95%) of the ester. Rf = 0.30 (EtOAc/heptane, 3:7); m.p.
Methyl (E)-4-Benzyloxy-6-(3-hydroxyprop-1-enyl)-1,3-benzodioxole-
5-carboxylate (10): Carboxylic acid 9 (9.369 g, 26.3 mmol) was dis-
solved in THF (98 mL) under Ar and cooled to –6 °C, where Et3N
(4.8 mL, 34.2 mmol) was added. Ethyl chloroformate (3.0 mL,
31.6 mmol) was added dropwise and the suspension was stirred for
2 h at –5 to –2 °C. The mixture was filtered and the filter cake
washed with THF (120 mL). To the filtrate was added H2O (16 mL)
and the solution was cooled to 0 °C followed by dropwise addition
of NaBH4 (34.2 mL, 2  in triglyme, 68.4 mmol) with the tempera-
ture not exceeding 1 °C. The reaction was stirred for 2.5 h at 0 °C
and then quenched with 1  HCl (55 mL). The THF was removed
in vacuo and the residue poured into 1  HCl (95 mL) and ex-
tracted twice with toluene (400 and 200 mL). The combined or-
ganic phases were washed with H2O (4ϫ500 mL) and concentrated
in vacuo to yield 8.579 g (95 %) of the allyl alcohol. Rf = 0.20
159–160 °C (ref.[23a] 155–157 °C). IR (KBr): ν = 3006, 2947, 1666,
˜
1503, 1490, 1340, 1301, 1194, 1081, 1036, 986 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 11.00 (s, 1 H), 7.19 (s, 1 H), 6.07 (s, 2 H),
3.96 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.7, 152.6,
146.8, 135.6, 115.4, 112.4, 102.9, 84.6, 51.9 ppm. C9H7IO5 (322.1):
calcd. C 33.56, H 2.19; found C 33.43, H 2.13. HRMS: calcd. for
C9H7IO5Na [M + Na]+ m/z 344.9230; found m/z 344.9232. NMR
spectroscopic data are in accordance with literature values.[23]
(EtOAc/heptane, 1:1); m.p. 88 °C. IR (KBr): ν = 3400–3100, 3008,
˜
2896, 2850, 1727, 1611, 1483, 1472, 1428, 1375, 1292, 1247, 1142,
1
1079, 1031 cm–1. H NMR (300 MHz, CDCl3): δ = 7.42–7.29 (m,
5 H), 6.74 (s, 1 H), 6.51 (dt, J = 1.5, 15.6 Hz, 1 H), 6.19 (dt, J =
5.6, 15.7 Hz, 1 H), 5.97 (s, 2 H), 5.23 (s, 2 H), 4.25 (dd, J = 1.1,
5.6 Hz, 2 H), 3.83 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.8, 150.3, 139.2, 136.8, 136.2, 130.5, 129.9, 128.3, 128.1, 127.8,
127.0, 120.8, 101.6, 100.2, 74.1, 63.5, 52.4 ppm. C19H18O6 (342.4):
calcd. C 66.66, H 5.30; found C 66.29, H 5.21. HRMS: calcd. for
C19H19O6 [M + H]+ m/z 343.1182; found m/z 343.1163.
Methyl 4-Hydroxy-6-iodo-1,3-benzodioxole-5-carboxylate (8):
Phenol 7 (19.0 g, 59.0 mmol) was dissolved in DMF (500 mL) un-
der Ar and cooled to 0 °C. NaH (4.0 g, 55–65% in mineral oil,
88.5 mmol) was added in small portions and the suspension was
stirred for 20 min followed by addition of BnBr (14.0 mL,
118 mmol). The mixture was stirred at ambient temperature over-
night, quenched with H2O and poured into Et2O (500 mL). The
solution was washed with H2O (4ϫ1 L) and the combined aqueous
layers were extracted with Et2O (2ϫ500 mL). The combined or-
ganic phases were concentrated and co-concentrated with toluene.
The residue was purified by dry column vacuum chromatog-
raphy[29] (EtOAc/heptane, 1:9) to yield 24.3 g (quantitative). Rf =
Methyl (E)-4-Benzyloxy-6-(3-bromoprop-1-enyl)-1,3-benzodioxole-
5-carboxylate (11): Allyl alcohol 10 (2.716 g, 7.93 mmol) was dis-
solved in THF (30 mL) under Ar followed by addition of Et3N
(1.8 mL, 12.9 mmol) and LiBr (2.02 g, 23.3 mmol). The solution
was cooled to –40 °C and Ms2O (2.08 g, 11.9 mmol) was added.
The suspension was warmed to room temperature over 4 h (the
cooling bath was removed after 1 h at –10 °C). The reaction was
quenched with 4.8 % HBr (50 mL) and extracted with EtOAc
(50 mL + 3 ϫ30 mL). The combined organic phases were dried
with MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (EtOAc/heptane, 1:3) to yield
2.973 g (93%) of a white solid (unstable on dry SiO2). Rf = 0.58
0.42 (EtOAc/heptane, 3:7); m.p. 106–107 °C. IR (KBr): ν = 3029,
˜
2948, 2912, 1727, 1617, 1466, 1374, 1346, 1271, 1134, 1088, 1037
1
cm–1. H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 6.96
(s, 1 H), 5.97 (s, 2 H), 5.24 (s, 2 H), 3.87 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.4, 150.7, 139.9, 137.4, 136.4, 128.4,
128.2, 127.9, 127.8, 113.4, 101.9, 81.0, 74.3, 52.7 ppm. C16H13IO5
(412.2): calcd. C 46.62, H 3.18; found C 46.48, H 3.11. MS: m/z =
434.9 [M + Na]+.
(EtOAc/heptane, 1:1); m.p. 69.5–71 °C. IR (KBr): ν = 3026, 2968,
˜
2894, 1722, 1607, 1497, 1477, 1380, 1290, 1259, 1195, 1146, 1095,
1
1030 cm–1. H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H),
6.76 (s, 1 H), 6.56 (d, J = 15.4 Hz, 1 H), 6.24 (dt, J = 7.8, 15.4 Hz,
Methyl (E)-4-Benzyloxy-6-(2-carboxyvinyl)-1,3-benzodioxole-5- 1 H), 5.98 (s, 2 H), 5.24 (s, 2 H), 4.09 (dd, J = 0.9, 7.8 Hz, 2 H),
carboxylate (9): Iodide 8 (1.00 g, 2.43 mmol) was dissolved in DMF
3.85 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.4, 150.4,
(10 mL) under Ar and the mixture degassed by sonication. Bu3N
139.3, 136.8, 136.7, 130.4, 128.9, 128.4, 128.1, 127.8, 126.8, 121.2,
4670
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4666–4673

Convergent Synthesis of Pancratistatin from Piperonal and Xylose
101.7, 100.3, 74.1, 52.4, 33.0 ppm. C19H17BrO5 (405.3): calcd. C
56.31, H 4.23; found C 56.10, H 4.13. HRMS: calcd. for
C19H18BrO5 [M + H]+ m/z 405.0338; found m/z 405.0362.
DBU (0.15 mL, 1.00 mmol). The solution was warmed to –20 °C
over 1 h where it was quenched with 12% aqueous NH4Cl (30 mL).
After separating the phases, the aqueous phase was extracted with
CH2Cl2 (3ϫ10 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography (EtOAc/heptane, 1:4) to yield
0.3729 g (98 %) of a white foam. The imidate (0.2563 g,
0.416 mmol) was heated neat to 135 °C in an oil bath under high
vacuum (≈ 0.1 Torr) for 21 h. The residue was purified by flash
chromatography (EtOAc/heptane, 1:4) to yield 166.9 mg (65%) of
a white solid (64% over two steps). Rf = 0.46 (EtOAc/heptane, 1:1).
Decomposes Ͼ 145 °C (ref.[11] m.p. 186–187 °C). [α]2D1 = –30.0 (c =
(3R,4R,4aR,11bS)-4,7-Dibenzyloxy-3-hydroxy-3,4,4a,11b-tetra-
hydro-6H-[1,3]benzodioxolo[5,6-c]chromen-6-one (14): Iodide 12[18]
(1.0036 g, 2.10 mmol) was dissolved in THF (30 mL) under Ar in
a 100 mL conical flask and water (10 mL) was added. After ad-
dition of activated Zn (1.371 g, 21.0 mmol) the suspension was son-
icated at 40–45 °C, while the allylating reagent 11 (1.271 g,
3.14 mmol) in THF (10 mL) was added by syringe pump over 5 h.
After the addition the mixture was sonicated for another 2 h and
then filtered through a pad of Celite, which was washed with
EtOAc (3ϫ20 mL). To the filtrate was added 12% aqueous NH4Cl
(50 mL) and the phases were separated. The aqueous phase was
extracted with more EtOAc (3ϫ20 mL) and the combined organic
phases were dried with MgSO4, filtered, and concentrated in vacuo.
The residue was dissolved in MeOH (50 mL) and stirred with Am-
berlite IR-120(H+) (15 mL) overnight. The resin was filtered off
and rinsed with acetone. The filtrate was concentrated in vacuo
and co-concentrated with toluene (2ϫ10 mL). The residue was dis-
solved in anhydrous CH3CN (25 mL), K2CO3 (1.037 g, 7.50 mmol)
was added and the suspension was refluxed under Ar for 1.5 h. The
mixture cooled to room temperature, diluted with CH2Cl2 (30 mL),
poured into 12 % aqueous NH4Cl (100 mL) and extracted with
CH2Cl2 (3ϫ20 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated in vacuo. The residue was dis-
solved in anhydrous CH2Cl2 (25 mL), degassed by sonication under
Ar and Hoveyda-Grubbs’ 2nd generation catalyst (37.7 mg,
60.2 µmol) was added. The solution was refluxed for 1.5 h under
Ar after which it was concentrated in vacuo and purified by flash
chromatography (EtOAc/heptane, 2:3 Ǟ 3:2) to yield 345 mg (35%)
of the desired diastereomer 14 and 318 mg (32%) of the undesired
15 as white foams.
1.0, CHCl ). IR (neat): ν = 3307, 3031, 2909, 2872, 1701, 1615,
˜
3
1478, 1305, 1264, 1246, 1088, 1053, 818 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 7.55–7.28 (m, 10 H), 6.80 (d, J = 9.2 Hz, 1 H), 6.44
(s, 1 H), 6.03 (m, 1 H), 6.00 (d, J = 1.4 Hz, 1 H), 5.93 (d, J =
1.3 Hz, 1 H), 5.88 (dd, J = 1.6, 10.2 Hz, 1 H), 5.38 (d, J = 11.4 Hz,
1 H), 5.32 (d, J = 11.3 Hz, 1 H), 4.69–4.64 (m, 2 H), 4.62 (d, J =
11.7 Hz, 1 H), 4.48–4.42 (m, 1 H), 4.10–4.06 (m, 1 H), 3.04 (dd, J
= 2.4, 9.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.4,
160.8, 152.8, 144.6, 138.5, 137.9, 137.2, 136.7, 130.8, 128.6, 128.3,
128.1, 128.0, 127.8, 126.5, 111.1, 103.2, 102.1, 92.3, 75.4, 74.5, 72.2,
70.7, 50.2, 38.9 ppm. HRMS: calcd. for C30H24Cl3NO7Na [M +
Na]+ m/z 638.0511; found m/z 638.0486. 1H NMR spectroscopic
data are in accordance with literature values.[11]
(1R,2S,3S,4R,4aR,11bR)-4,7-Dibenzyloxy-2,3-dihydroxy-1-(2,2,2-
trichloroacetylamino)-1,2,3,4,4a,11b-hexahydro-6H-[1,3]benzodi-
oxolo[5,6-c]chromen-6-one (17): Alkene 16 (163.3 mg, 0.265 mmol)
was dissolved in THF (2.65 mL), and NMO (68.0 mg,
0.581 mmol), H2O (0.2 mL) and OsO4 (18.4 mg, 72.4 µmol) were
added. The solution was stirred in a closed vial for 123 h at room
temperature and then poured into 10% aqueous Na2SO3 (20 mL)
and EtOAc (5 mL). The phases were separated and the aqueous
layer extracted with EtOAc (3ϫ10 mL). The combined organic
phases were dried with MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (CH2Cl2/MeOH,
49:1 Ǟ 24:1) to yield a white solid (161.7 mg, 94%). Rf = 0.10
14: Rf = 0.24 (EtOAc/heptane, 1:1). [α]2D3 = –113.6 (c = 1.07, CHCl3)
[ref.[12f] [α]2D5 = –74.3 (c = 0.14, CHCl )]. IR (KBr): ν = 3600–3170,
˜
3
3026, 2913, 1718, 1610, 1472, 1369 1262, 1184, 1118, 1046, 933,
1
733, 697 cm–1. H NMR (500 MHz, CDCl3): δ = 7.56–7.27 (m, 10
(EtOAc/heptane, 1:1); m.p. 201–202 °C (ref.[11] 202–206 °C). [α]2D1
=
H), 6.50 (s, 1 H), 6.04 (d, J = 1.1 Hz, 1 H), 5.99 (d, J = 1.1 Hz, 1
H), 5.76–5.71 (m, 1 H), 5.48–5.44 (m, 1 H), 5.34 (d, J = 11.4 Hz,
1 H), 5.29 (d, J = 11.3 Hz, 1 H), 4.76–4.69 (m, 3 H), 4.56–4.51 (m,
1 H), 4.15–4.09 (m, 1 H), 3.57–3.53 (m, 1 H), 2.45 (d, J = 11.0 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.2, 153.3, 143.9,
138.9, 138.0, 137.2, 136.7, 129.8, 128.7, 128.3, 128.0, 125.8, 111.5,
102.5, 102.0, 74.8, 74.5, 74.1, 73.9, 64.7, 35.4 ppm. HRMS: calcd.
for C28H24O7Na [M + Na]+ m/z 495.1415; found m/z 495.1414. 1H
NMR spectroscopic data are in accordance with literature val-
ues.[11,12f]
+30.0 (c = 1.0, DMSO). IR (KBr): ν = 3600–3150, 3025, 2923,
˜
1713, 1701, 1610, 1472, 1374, 1297, 1256, 1092 cm–1. 1H NMR
(500 MHz, CDCl3 + 2 drops of CD3OD): δ = 7.48–7.24 (m, 10 H),
6.43 (s, 1 H), 5.96 (d, J = 1.1 Hz, 1 H), 5.85 (d, J = 1.0 Hz, 1 H),
5.32 (d, J = 11.4 Hz, 1 H), 5.26 (d, J = 11.4 Hz, 1 H), 4.64 (d, J =
11.7 Hz, 1 H), 4.59–4.55 (m, 2 H), 4.25–4.22 (m, 1 H), 4.14 (dd, J
= 3.1, 10.7 Hz, 1 H), 4.02 (t, J = 2.7 Hz, 1 H), 3.97 (t, J = 11.1 Hz,
1 H), 3.34 (dd, J = 2.7, 11.4 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3 + 2 drops of CD3OD): δ = 162.7, 161.0, 152.9, 143.9, 138.2,
137.0, 136.8, 136.6, 128.4, 128.2, 128.0, 127.9, 127.8, 127.6, 110.7,
104.2, 102.0, 92.5, 76.3, 75.8, 74.4, 72.7, 70.7, 69.1, 52.0, 39.5 ppm.
HRMS: calcd. for C30H26Cl3NO9Na [M + Na]+ m/z 672.0565;
found m/z 672.0540. 1H NMR spectroscopic data are in accordance
with literature values.[11]
1
15: Rf = 0.08 (EtOAc/heptane, 1:1). H NMR (300 MHz, CDCl3):
δ = 7.55–7.24 (m, 10 H), 6.46 (s, 1 H), 6.08–6.01 (m, 1 H), 6.01 (d,
J = 1.2 Hz, 1 H), 5.97 (d, J = 1.2 Hz, 1 H), 5.44 (d, J = 9.9 Hz, 1
H), 5.29 (s, 2 H), 4.89 (d, J = 12.0 Hz, 1 H), 4.86–4.83 (m, 1 H),
4.67 (d, J = 12.0 Hz, 1 H), 4.39 (m, 1 H), 3.66 (dd, J = 1.6, 5.2 Hz,
1 H), 3.36 (br. s, 1 H), 2.99 (d, J = 10.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.6, 153.3, 143.8, 138.0, 137.9, 137.7,
136.7, 129.5, 128.4, 128.2, 127.9, 127.8, 127.7, 124.8, 111.3, 102.0,
101.9, 75.6, 74.3, 74.1, 69.9, 63.2, 40.0 ppm. HRMS: calcd. for
C28H24O7Na [M + Na]+ m/z 495.1415; found m/z 495.1409.
(1R,2S,3S,4R,4aR,11bR)-2,7-Dibenzyloxy-1,3,4-trihydroxy-
1,3,4,4a,5,11b-hexahydro-2H-[1,3]dioxolo[4,5-j]phenanthridin-6-one
(18): Lactone 17 (112.2 mg, 0.172 mmol) and K2CO3 (239 mg,
1.73 mmol) were suspended in anhydrous 5:2 MeOH/CH2Cl2
(7.0 mL) and the mixture was heated to reflux under Ar overnight.
The suspension was cooled to room temperature and carefully neu-
(1S,4R,4aR,11bR)-4,7-Dibenzyloxy-1-(2,2,2-trichloroacetylamino)- tralised with Amberlite IR-120 (H+). The resin was filtered off,
1,4,4a,11b-tetrahydro-6H-[1,3]benzodioxolo[5,6-c]chromen-6-one
(16): Alcohol 14 (0.2912 g, 0.616 mmol) was dissolved in anhydrous
CH2Cl2 (5.0 mL) under Ar and cooled to –42 °C, where Cl3CCN
(0.31 mL, 3.09 mmol) was added followed by dropwise addition of
washed with 1:1 MeOH/CH2Cl2 and the solvent was removed in
vacuo. The residue was dissolved in CH2Cl2 (8.0 mL), HOBt
(55.5 mg, 0.411 mmol) was added and the solution was cooled to
–5 °C under Ar. DCC (43.2 mg, 0.209 mmol) was then added and
Eur. J. Org. Chem. 2009, 4666–4673
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4671

J. H. Dam, R. Madsen
FULL PAPER
Shannon, E. M. Schubert, J. Dare, B. Ugarkar, M. A. Ussery,
M. J. Phelan, J. Nat. Prod. 1992, 55, 1569–1581.
the mixture was stirred for 5 min before the cooling bath was re-
moved and the reaction was warmed to room temperature over 1 h.
The solvent was removed in vacuo and the residue was purified
by flash chromatography (CH2Cl2/MeOH, 99:1 Ǟ 24:1) to afford
71.0 mg (81%) of a solid. Rf = 0.40 (CH2Cl2/MeOH, 19:1); m.p.
93–94 °C (ref.[11] 98–100 °C). [α]2D1 = +52.0 (c = 1.0, CHCl3). IR
[5]
M. Ouarzane-Amara, J.-F. Franetich, D. Mazier, G. R. Pettit,
L. Meijer, C. Doerig, I. Desportes-Livage, Antimicrob. Agents
Chemother. 2001, 45, 3409–3415.
A. McLachlan, N. Kekre, J. McNulty, S. Pandey, Apoptosis
2005, 10, 619–630.
a) S. D. Shnyder, P. A. Cooper, N. J. Millington, J. H. Gill,
M. C. Bibby, J. Nat. Prod. 2008, 71, 321–324; b) G. R. Pettit,
N. Melody, D. L. Herald, J. Nat. Prod. 2004, 67, 322–327; c)
G. R. Pettit, B. Orr, S. Ducki, Anti-Cancer Drug Des. 2000, 15,
389–395.
a) J. McNulty, J. J. Nair, C. Griffin, S. Pandey, J. Nat. Prod.
2008, 71, 357–363; b) A. S. Kireev, O. N. Nadein, V. J. Agustin,
N. E. Bush, A. Evidente, M. Manpadi, M. A. Ogasawara, S. K.
Rastogi, S. Rogelj, S. T. Shors, A. Kornienko, J. Org. Chem.
2006, 71, 5694–5707; c) T. Hudlicky, M. Moser, S. C. Banfield,
U. Rinner, J.-C. Chapuis, G. R. Pettit, Can. J. Chem. 2006, 84,
1313–1337; d) J. McNulty, V. Larichev, S. Pandey, Bioorg. Med.
Chem. Lett. 2005, 15, 5315–5318; e) G. R. Pettit, N. Melody, J.
Nat. Prod. 2005, 68, 207–211; f) U. Rinner, T. Hudlicky, H.
Gordon, G. R. Pettit, Angew. Chem. Int. Ed. 2004, 43, 5342–
5346; g) U. Rinner, H. L. Hillebrenner, D. R. Adams, T. Hud-
licky, G. R. Pettit, Bioorg. Med. Chem. Lett. 2004, 14, 2911–
2915; h) T. Hudlicky, U. Rinner, D. Gonzales, H. Akgun, S.
Schilling, P. Siengalewicz, T. A. Martinot, G. R. Pettit, J. Org.
Chem. 2002, 67, 8726–8743; i) J. McNulty, J. Mao, R. Gibe, R.
Mo, S. Wolf, G. R. Pettit, D. L. Herald, M. R. Boyd, Bioorg.
Med. Chem. Lett. 2001, 11, 169–172.
[6]
[7]
(neat): ν = 3500–3200, 2904, 1644, 1612, 1475, 1453, 1366, 1335,
˜
1
1285, 1218, 1069, 1030, 730 cm–1. H NMR (500 MHz, CDCl3): δ
= 8.03 (s, 1 H), 7.54–7.23 (m, 10 H), 6.66 (s, 1 H), 5.95 (d, J =
1.5 Hz, 1 H), 5.94 (d, J = 1.5 Hz, 1 H), 5.27 (d, J = 11.2 Hz, 1 H),
5.23 (d, J = 11.3 Hz, 1 H), 4.98 (br. s, 1 H), 4.64 (d, J = 11.8 Hz,
1 H), 4.59 (d, J = 11.8 Hz, 1 H), 4.45 (br. s, 1 H), 4.25 (br. s, 1 H),
4.05 (t, J = 3.0 Hz, 1 H), 4.01–3.97 (m, 2 H), 3.82 (dd, J = 10.1,
13.0 Hz, 1 H), 3.10 (d, J = 13.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.4, 152.0, 143.1, 137.6, 137.5, 136.9, 136.5, 128.5,
128.4, 128.3, 128.0, 127.9, 127.5, 116.2, 101.7, 101.1, 76.7, 74.9,
72.4, 71.4, 71.0, 67.6, 49.9, 41.5 ppm. HRMS: calcd. for
[8]
1
C28H27NNaO8 [M + Na]+ m/z 528.1630; found m/z 528.1621. H
NMR spectroscopic data are in accordance with literature val-
ues.[11]
Pancratistatin: Dibenzyl ether 18 (34.2 mg, 67.7 µmol) was dis-
solved in EtOAc (2.0 mL) and Pd(OH)2/C (104 mg) was added. The
suspension was degassed and stirred while H2 was bubbled through
for 2 h (1.0 mL of EtOAc was added after 1.5 h). The mixture was
stirred under an H2 atmosphere for an additional 2 h and then
filtered through a small plug of Celite, which was rinsed with 40%
MeOH in CH2Cl2. The solvent was removed in vacuo to afford
22.0 mg (99%) of a white solid. Rf = 0.24 (CH2Cl2/MeOH, 9:1).
Decomposes above 250 °C. [α]2D1 = +37 (c = 1.0, DMSO) [ref.[2a]
[α]3D4 = +48 (c = 1.0, DMSO), ref.[12e] [α]2D3 = +38 (c = 1.08, DMSO),
ref.[12g] [α]2D6 = +40.9 (c = 1.0, DMSO), ref.[12h] [α]2D5 = +44.0 (c =
[9]
G. R. Pettit, G. R. Pettit III, G. Groszek, R. A. Backhaus,
D. L. Doubek, R. J. Barr, A. W. Meerow, J. Nat. Prod. 1995,
58, 756–759.
For a recent review, see: M. Manpadi, A. Kornienko, Org. Prep.
Proced. Int. 2008, 40, 107–161.
[10]
[11]
[12]
S. Danishefsky, J. Y. Lee, J. Am. Chem. Soc. 1989, 111, 4829–
4837.
1.0, DMSO)]. IR (neat): ν = 3348, 2926, 1671, 1615, 1597, 1462,
˜
1416, 1347, 1296, 1228, 1082, 1065, 1036, 876 cm–1. 1H NMR
(500 MHz, [D6]DMSO): δ = 13.06 (s, 1 H), 7.50 (s, 1 H), 6.49 (s, 1
H), 6.06 (s, 1 H), 6.04 (s, 1 H), 5.36 (d, J = 4.0 Hz, 1 H), 5.08 (d,
J = 5.8 Hz, 1 H), 5.05 (d, J = 6.1 Hz, 1 H), 4.83 (d, J = 7.5 Hz, 1
H), 4.28 (m, 1 H), 3.97 (m, 1 H), 3.85 (m, 1 H), 3.74–3.67 (m, 2
H), 2.97 (br. d, J = 11.8 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 169.4, 152.0, 145.3, 135.6, 131.6, 107.4, 101.7, 97.6,
73.2, 70.1, 69.9, 68.4, 50.4, 39.5 (assigned by HSQC) ppm. HRMS:
calcd. for C14H16NO8 [M + H]+ m/z 326.0870; found m/z 326.0864.
NMR spectroscopic data are in accordance with literature val-
ues.[11,12c].
a) M. Li, A. Wu, P. Zhou, Tetrahedron Lett. 2006, 47, 3707–
3710; b) H. Ko, E. Kim, J. E. Park, D. Kim, S. Kim, J. Org.
Chem. 2004, 69, 112–121; c) G. R. Pettit, N. Melody, D. L. Her-
ald, J. Org. Chem. 2001, 66, 2583–2587; d) J. H. Rigby, U. S. M.
Maharoof, M. E. Mateo, J. Am. Chem. Soc. 2000, 122, 6624–
6628; e) P. Magnus, I. K. Sebhat, Tetrahedron 1998, 54, 15509–
15524; f) T. J. Doyle, M. Hendrix, D. VanDerveer, S. Javan-
mard, J. Haseltine, Tetrahedron 1997, 53, 11153–11170; g) T.
Hudlicky, X. Tian, K. Königsberger, R. Maurya, J. Rouden, B.
Fan, J. Am. Chem. Soc. 1996, 118, 10752–10765; h) B. M.
Trost, S. R. Pulley, J. Am. Chem. Soc. 1995, 117, 10143–10144.
a) L. Hyldtoft, R. Madsen, J. Am. Chem. Soc. 2000, 122, 8444–
8452; b) L. Hyldtoft, C. S. Poulsen, R. Madsen, Chem. Com-
mun. 1999, 2101–2102.
For a review, see: R. Madsen, Eur. J. Org. Chem. 2007, 399–
415.
a) R. N. Monrad, C. B. Pipper, R. Madsen, Eur. J. Org. Chem.
2009, 3387–3395; b) R. Csuk, E. Prell, S. Reissmann, Tetrahe-
dron 2008, 64, 9417–9422; c) P. R. Skaanderup, R. Madsen,
J. Org. Chem. 2003, 68, 2115–2122; d) F.-D. Boyer, I. Hanna,
Tetrahedron Lett. 2001, 42, 1275–1277.
R. N. Monrad, M. Fanefjord, F. G. Hansen, N. M. E. Jensen,
R. Madsen, Eur. J. Org. Chem. 2009, 396–402.
F. G. Hansen, E. Bundgaard, R. Madsen, J. Org. Chem. 2005,
70, 10139–10142.
A. E. Håkansson, A. Palmelund, H. Holm, R. Madsen, Chem.
Eur. J. 2006, 12, 3243–3253.
E. Dalcanale, F. Montanari, J. Org. Chem. 1986, 51, 567–569.
V. Snieckus, Chem. Rev. 1990, 90, 879–933.
R. S. C. Lopes, C. C. Lopes, C. H. Heathcock, Tetrahedron
Lett. 1992, 33, 6775–6778.
[13]
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for compounds 2–11, 14–18
and pancratistatin.
[14]
[15]
Acknowledgments
We thank the Danish National Research Foundation for financial
support.
[16]
[17]
[18]
[1] G. R. Pettit, V. Gaddamidi, G. M. Cragg, D. L. Herald, Y. Sa-
gawa, J. Chem. Soc., Chem. Commun. 1984, 1693–1694.
[2] a) G. R. Pettit, V. Gaddamidi, D. L. Herald, S. B. Singh, G. M.
Cragg, J. M. Schmidt, F. E. Boettner, M. Williams, Y. Sagawa,
J. Nat. Prod. 1986, 49, 995–1002; b) G. R. Pettit, V. Gaddamidi,
G. M. Cragg, J. Nat. Prod. 1984, 47, 1018–1020.
[3] G. R. Pettit, G. R. Pettit III, R. A. Backhaus, M. R. Boyd,
A. W. Meerow, J. Nat. Prod. 1993, 56, 1682–1687.
[4] B. Gabrielsen, T. P. Montath, J. W. Huggins, D. F. Kefauver,
G. R. Pettit, G. Groszek, M. Hollingshead, J. J. Kirsi, W. M.
[19]
[20]
[21]
[22]
D. Crich, V. Krishnamurthy, Tetrahedron 2006, 62, 6830–6840.
4672
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4666–4673

Convergent Synthesis of Pancratistatin from Piperonal and Xylose
[23] a) G. E. Keck, M. D. McLaws, T. T. Wager, Tetrahedron 2000,
56, 9875–9883; b) G. E. Keck, T. T. Wager, J. F. D. Rodriquez,
J. Am. Chem. Soc. 1999, 121, 5176–5190.
[24] T. Jeffery, Tetrahedron 1996, 52, 10113–10130.
[25] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
Am. Chem. Soc. 2000, 122, 8168–8179.
[26] For details of the enzymatic assays, see: S. M. Andersen, C.
Ekhart, I. Lundt, A. E. Stütz, Carbohydr. Res. 2000, 326, 22–
33.
[27]
[28]
A. D. Buss, S. Warren, J. Chem. Soc. Perkin Trans. 1 1985,
2307–2325.
M. Khaldi, F. Chrétien, Y. Chapleur, Bull. Soc. Chim. Fr. 1996,
133, 7–13.
[29] D. S. Pedersen, C. Rosenbohm, Synthesis 2001, 2431–2434.
Received: June 29, 2009
Published Online: August 6, 2009
Eur. J. Org. Chem. 2009, 4666–4673
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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