Total synthesis of S-(+)-argentilactone

Article abstract of DOI:10.1515/znb-2001-0318

Asymmetric total synthesis of S-(+)-argentilactone (2) was accomplished, using methyl-α-D-glucopyranoside (3) as carbohydrate template. Benzylidene acetal 5 was hydrolysed with ^tBuOOH/AlCl₃ and further manipulated to produce the alde

Full text of DOI:10.1515/znb-2001-0318

Total Synthesis of S-(+)-Argentilactone
Muhammad Saeed3, M uhamm ad A bbas3, Khalid M ohammad Khanb, and
Wolfgang Voelter3
a Abteilung für Physikalische Biochemie, Physiologisch-chemisches Institut der
Universität Tübingen, Hoppe-Seyler-Straße-4, D-72076 Tübingen, Germany
b International Center for Chemical Sciences, H. E. J. Research Institute of Chemistry,
University of Karachi, Karachi-75276, Pakistan
Reprint request to Prof. W. Voelter. E-mail: wolfgang.voelter@uni-tuebingen.de
Dedicated to Professor Gerard Descotes, Universite Claude Bernard, Lyon 1, France
Z. Naturforsch. 56b, 325-328 (2001); received December 16, 2000
Argentilactone, Carbohydrate Templates, Asymmetrie Total Synthesis
Asymmetrie total synthesis of S-(+)-argentilactone (2) was accomplished, using methyl-a-
D-glucopyranoside (3) as carbohydrate template. Benzylidene acetal 5 was hydrolysed with
fBuOOH/AlCl3 and further manipulated to produce the aldehyde 10. A Wittig reaction and
subsequent oxidation of the anomeric position yielded the target argentilactone.
Introduction
be further elaborated to the syntheses of natural
products [10]. Continuing our research in this
context, we decided to design a strategy for the
synthesis of a,/?-unsaturated 6-lactones.
Argentilactone (1), an a,/?-unsaturated <5-lac-
tone, was originally isolated in 1977 from the rhi-
zomes of Aristolochia argentina Gris [1]. This com-
pound is the m ajor constituent of the essential oil
and hexane extract of Annona haematantha [2]
and also present in the methanolic extract of the
leaves of Chorisia crispiflora [3]. The biological
Results and Discussion
The stereochemistry at C-6 (pyran numbering)
of 1 is R which requires a sugar from the L-series.
studies on 1 have revealed high antileishmanial [2] Nevertheless, to confirm the absolute stereochem -
and cytotoxic activity against P-388 mouse leukae- istry of 1 and to test its biological activity, we de-
scribe here an asymmetric total synthesis of 5-(+)-
argentilactone (2).
According to H older and Fraser-Reid [11], 3
was efficiently converted into methyl-4,6-di-O-
benzylidene-a-D-glucopyranoside (4) in 90%
yield. The spectroscopic data were found to be ex-
mia cells [3]. M oreover, it can also be used as start-
ing material for the synthesis of interesting phero-
mones [4]- These features prom pted us to
undertake the total synthesis of this compound.
Although some racemic as well as enantiopure
syntheses of natural argentilactone (1) have been
reported [5-8], the enantiopure synthesis of non- actly identical with those already reported [12],
natural argentilactone (2) did not appear in the
literature so far. H erein we report on the first total
synthesis of non-natural S-(+)-argentilactone (2).
The vicinal diol in 4 is now ready to undergo 2,3-
dideoxygenation and we found iodoform/imidaz-
ole/ triphenyphosphine in toluene [13] to be an
In the past we have used carbohydrate tem - excellent reagent (87% yield) to produce 5 as
white crystals. A t this stage, we found that fBu-
OOH/AICI3 in dichloromethane can hydrolyse the
plates [9] for the stereoselective synthesis of biolo-
gically interesting chiral building blocks that can
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326
M. Saeed et al. • Total Synthesis of S-(+)-Argentilactone
further purification. Compounds 4[11], 5[13], 7
and 8[14] were prepared according to literature
procedures. Solvents were dried and distilled ac-
cording to standard methods. Column chromatog-
raphy was perform ed on silica gel 60 (Merck,
0.063-0.200 mm) using the indicated solvent sys-
tem. *H and 13C NM R spectra were recorded in
CDC13 on a Bruker AC 250 spectrom eter with
tetramethylsilane as internal standard. The chemi-
cal shifts are reported in parts per million (ppm).
Mass spectra were recorded on a Finnigan MAT
312 mass spectrom eter, connected to a PDO 11/34
(DEC) com puter system. Optical rotations were
obtained with an LEP A Z polarim eter (Zeiss,
Jena) at 546 nm. All melting points are uncor-
rected.
acetal function to produce 6 in good yield. Further
reactions in this regard are still under investiga-
tion. Selective protection of the diol 6 at the pri-
mary position with benzoyl chloride at 0 °C and
mesylation of the secondary alcohol generated 8
in 90% yield via two steps [14]. The mesyl group
was displaced with superhydride® (LiBHEt3) in
THF. The presence of a CH 2 signal at d = 26 ppm
in the 13C NM R spectrum (GASPE) and
a
multiplet around = 2.0 ppm in the *H NMR
6
spectrum confirmed the deoxygenation at C-4 of
the alcohol 9. Swern oxidation of 9 generated the
aldehyde 10, and subsequent Wittig reaction of 10
with hexyltriphenylphosphonium bromide intro-
duced the double bond between C-7 and C-8 in
the final compound. The cis stereochemistry of the
double bond is indicated by the low coupling con-
stant (/ = 10.3 Hz). Finally, 11 was oxidized at the
anomeric position with aqueous H 20 2 in the pres-
ence of a catalytic amount of M0 O 3 [15] to gener-
ate the target argentilactone in -30% overall yield
from 3. All spectroscopic data correlate with the
reported natural product 1, except the optical ro-
tation, which is opposite to that reported for 1.
M ethyl 2,3-didehydro-2,3-dideoxy-a-D -
erythro-hexoside (6 )
To a stirred solution of 5 [13] (20 g, 0.08 mol)
in absolute CH2C12 (100 ml) was added anhydrous
fBuO O H (14.5 ml, 5.5 M in decane) under nitro-
gen. A fter 10 min was added A1C13 (10.7 g, 0.08
mol). Stirring was continued at the same tem per-
ature till TLC analysis showed no starting m ater-
ial. The reaction was quenched with slow addition
of water and extracted with CH2C12 (2 x 100 ml).
The combined organic layers were dried (Na2S 0 4)
and evaporated under low pressure to yield almost
pure 5 (10.3 g, 0.06 mol) as a colourless oil, [a]o
Experimental
All chemicals and reagents were obtained from
commercial suppliers and used as such without
0-^V r^ 0'V .»OCH3
0^ vY^°'Y„tOCH3
—
vOCH,
0 nV«"OCH3
H° Nyx'°x...i»tOCH3
*—
-
T
j
-
9
10
7 Rj * OBz, Rj * OH
8 Rj ■ OBz, R2 » OMs
.CL
2
/
— "\
Y ^ ° \...» och3
ix
viii
11
Scheme 1. Reagents and conditions', i, PhCH(OMe)2, p-TsOH, DMF, reflux under reduced pressure, lh, 97% (ref.
11); ii, PPh3, imidazole, CHI3. toluene, reflux, 2 h, 87% (ref. 13); iii, A1C13, 'BuOOH, CH2C12, -40 °C, 30 min, 80%;
iv, PhCOCl, pyridine, 0 °C, 8 h, 90%; v, MsCl, pyridine, 5 °C, 4 h, 95% (ref. 14); vi, LiBHEt3, THF, 12 h, 70%; vii,
oxalyl chloride, DMSO, -40 °C, Et3N, 1 h, 90%; viii, C6H13PPh3Br, BuLi, 80%; ix, aq H20 2, M o03 and then Ac20,
pyridine, 70%.
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M. Saeed et al. • Total Synthesis of S-(+)-Argentilactone
327
+104.3 (c - 1, m ethanol). *H NM R (250 MHz,
CDC13): (5 = 3.00 (br s, 1 H , O H ), 3.44 (s, 3 H,
OMe), 3.64-3.72 (m, 1 H, 5-H), 3.86 (br s, 2 H, 6-
H, 6 '-H), 4.18 (m, 1 H, 4-H), 4.87 (br s, 1 H, 1-H),
5.74 (dt, J = 2.46, 10.2 Hz, 1 H, 3-H), 5.96 (d, J =
10.2 Hz, 1 H, 2-H). FAB-MS: m /z = 159.0 (18%)
oil. - !H NMR (250 MHz, CDC13): <5 = 2.10-2.22
(m, 2 H, 4-H), 3.75 (s, 3 H, OM e), 4.40 (dd, J =
4.8, 10.1 Hz, 1H, 5-H), 5.19 (d, J = 2.6 Hz, 1 H, 1-
H), 5.79-5.68 (m, 1 H, 3-H), 5.91-6.08 (m, 1H, 2-
H), 9.71 (s, 1H, 6-H). - FAB-MS: m /z = 141.1
(40%) [M+-l]. - C7H 10O 3 (142.06): calcd. C 59.14,
H 7.09; found C 59.07, H 7.00.
[M+-l].
-
C7H 120 4 (160.07): calcd. C 52.49, H
7.55; found C 52.31, H 7.40.
(2S)-H ept-l-enyl-(6S)-m ethoxy-3,6-dihydro-2H -
(2S)-M ethoxy-(6S) -hydroxym ethyl-5,6-dihydro-
pyran (11)
2H-pyran (9)
A solution of hexyltriphenylphosphonium bro-
mide (15.34 g, 40 mmol) in THF-HM PA (2:1,
150 ml) was cooled to -5 0 °C and n-BuLi (25 ml,
1.6 M in hexane) was added via a syringe. A fter
stirring several min at the same tem perature, a so-
lution of aldehyde 10 (5.0 g, 35.2 mmol) in TH F
(25 ml) was added to the reaction mixture via a
syringe. The solution was allowed to warm to -
10 °C over 45 min, petroleum ether was added,
To a stirred solution of 8 [14] (19.5 g, 0.057 mol)
in dry TH F superhydride® (5 ml, IM in TH F) was
added at 0 °C under nitrogen. The tem perature
was slowly raised to 40 °C. A fter 3 h the TLC
showed no starting material. Excess hydride was
destroyed with slow addition of water, then a 3 N
N aO H solution (10 ml) was added, followed by
the addition of a 30% aqueous H 20 2 solution
(10 ml). The mixture was than brought into a sepa- followed by extraction with water, aqueous
ratory funnel and the TH F layer was collected.
The aqueous layer was further extracted with
ether, the combined organic layers were dried
(Na2S 0 4) and the solvent was removed. After
flash chromatography with 5% ethyl acetate in
CH2C12 9 (5.76 g, 70%) was obtained as a col-
N aH C 03 and finally with water. The organic layer
was separated, dried and evaporated under re-
duced pressure. The residue was chrom atographed
on silica gel with CH2Cl2-hexane (80:20) to afford
pure 11 (6.09 g, 80%) as colourless oil, [a]D -50°
(c = 0.74, CH2C12). - 'H NM R (250 MHz, CDC13):
ourless oil, [a]o -75.3° (c = 0.74, C6H 6). - *H 6 = 0.89 (t, J = 6.9 Hz, 3H, CH3), 1.34 (m, 6H, 3 x
NM R (250 MHz, CDC13): <5 = 1.99-1.81 (m, 1 H,
4'-H ), 2.25-2.04 (m, 1 H, 4-H), 2.29 (brs, 1 H,
OH), 3.44 (s, 3 H, OM e), 3.82-3.54 (m, 2 H, 6 '-H,
5-H), 4.01 (m, 1 H, 6-H), 4.90 (d, J = 2.0 Hz, 1 H,
CH2), 2.01-2.30 (m, 4H, 2 x CH2), 3.38 (s, 3 H,
OCH 3), 3.75 (m, 1H, 6-H), 4.88 (br s, 1H, 2-H),
5.48 (m, 1 H, 10-H), 5.76 (m, 2H, 3-H, 9-H), 6.08
(m, 1H, 4-H). - FAB-MS: m /z = 210 (5% ) [M+]. -
1-H), 5.81-5.70 (m, 1 H, 3-H), 6.09-5.98 (m, 1 C i3H 220 2 (210.16): calcd. C 74.24, H 10.54; found
H, 2-H). EI-MS: m /z = 113 (100%) [M+-OMe]. -
C7H 120 3 (144.08): calcd. C 58.32, H 8.39; found C
58.25, H 8.35.
C 74.13, H 10.44.
(S)-(+)-Argendlactone (2)
To a suspension of 10 (6.0 g, 22 mmol) in aque-
ous 30% H 20 2 (250 ml) was added M o 0 3 (0.6 g).
The mixture was stirred at rt till completion of the
6-M ethoxy-3,6-dihydro-2H -pyran-2-carbaldehyde
(10)
A solution of oxalyl chloride (4 ml) in of CH2C12 reaction (TLC control). A fter disappearance of
(75 ml) was brought in a 250 ml three neck flask,
equipped with two dropping funnels, containing
the substrate, water (250 ml) was added and the
mixture extracted with CH2C12 (4x 50 ml). The
DM SO (6.8 ml) in CH 2C12 (20 ml) and alcohol 9 combined extracts were washed with water, dried,
(5.76 g, 40 mmol) in CH2C12 (40 ml). A t -7 8 °C
DMSO was slowly added. The mixture was stirred
for 2 min, then the alcohol was added within 5 min
and stirring continued for 15 min. Triethylamine
and concentrated to dryness, to afford an anom-
eric mixture of peroxide which was dissolved in
CH2C12 (25 ml) and added dropwise to a cooled
and stirred mixture (1:1) of acetic anhydride and
(30 ml) was added, the reaction mixture stirred for pyridine (50 ml) at <30 °C. The mixture was stored
at rt for 2 h, then poured on crushed ice and ex-
5 min and then allowed to warm to rt. W ater was
added and the organic phase removed. The aque- tracted with CH2C12 (3x30 ml). The combined ex-
ous layer was further extracted with CH 2C12 tracts were washed with sat. aq. N aH C 0 3 and
water, dried and concentrated to dryness, to afford
(50 ml), the organic layers were combined, dried,
and evaporated. The com pound was finally puri- 2 (2.99 g, 70% over two steps) as a yellow oil, [a]D
fied by flash chrom atography using pure CH2C12 +19.1 (c = 0.5, CH2C12). - ]H NM R (250 MHz,
as solvent to afford 10 (5.11 g, 90%) as a colourless
CDCI3): <3= 0.88 (t, 3 H, Me), 1.3 (m, 6 H, 3xCH2),
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328
M. Saeed et al. • Total Synthesis of S-(+)-Argentilactone
2.10 (m, 2 H, CH 2), 2.38 (m, 2 H, CH2), 5.0-5.8
(m, 3 H, 5-H, 6-H, 7-H), 6.04 (ddd, / = 10.3, 1.8
Hz, 1H, 2-H), 6.91 (ddd, / = 10.3, 4.2 Hz, 1H, 3-
H). - EI-MS: m /z = 194 (5% ) [M+]. - C12H 180 2
(194.27): calcd. C 79.19, H 9.34; found C 79.15,
H 9.30.
A cknow ledgem ent
We are thankful to the Deutscher A kade-
mischer Austauschdienst (D A A D ) for providing a
sandwich type scholarship to M. Saeed.
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