Synthesis of (R)-(-)-argentilactone

Article abstract of DOI:10.1016/S0957-4166(02)00138-6

A synthesis of (R)-(-)-argentilactone is reported starting from the (S)-enantiomer of glycidol. The synthesis is based on ring closing metathesis of the acrylic ester of (R)-1-O-(tert-butyldiphenylsilyl)-4-penten-1,2-diol 4.

Full text of DOI:10.1016/S0957-4166(02)00138-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 547–550
Synthesis of (R)-(−)-argentilactone
Trond Vidar Hansen*
School of Pharmacy, Department of Medicinal Chemistry, University of Oslo, PO Box 1185, N-0316 Blindern, Oslo, Norway
Received 27 February 2002; accepted 14 March 2002
Abstract—A synthesis of (R)-(−)-argentilactone is reported starting from the (S)-enantiomer of glycidol. The synthesis is based on
ring closing metathesis of the acrylic ester of (R)-1-O-(tert-butyldiphenylsilyl)-4-penten-1,2-diol 4. © 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
2. Results and discussions
Argentilactone 1 was first isolated in 1977 from the
Reaction of (S)-glycidol with tert-butyldiphenylsilyl-
chloride (TBDPS-Cl) and imidazole in DMF afforded
the silyl ether 2 in 95% yield (Scheme 1). The protected
glycidol was then subjected to an ethereal solution of
1
rhizomes of Aristolochia argentia, and exhibits both
2
antileishmanial activity and cytotoxic activity against
3
mouse leukemia cells. Its structure contains an a,b-
unsaturated d-lactone moiety with (R)-configuration at
the stereogenic center. This structural feature is also
present in several other biologically active natural prod-
8
the organocuprate reagent (CH CH) Cu(CN)(MgCl)
2
2
2
affording the homoallyl alcohol 3, which was then
treated with acryloyl chloride in THF in the presence of
Et N to give the ester 4 in 80% overall yield.
3
4
,6c
ucts that have been targets for syntheses.
There are a
5
few syntheses of (−)-argentilactone and its non-natural
enantiomer reported in the literature, as well as one of
the racemic compound. Usually, the (R)-stereogenic
6
We envisaged that compound 4 could be transformed
into the d-lactone ring using a ring closing metathesis
reaction. Treating the acryloyl ester 4 with 10% of
7
center has been introduced with carbohydrate building
5
a,b
blocks,
or the chirality has its origin from asymmet-
9
6b
Grubb’s catalyst, bis(tricyclohexylphosphine)benzyli-
ric reductions using enzymes.
dene ruthenium(IV) dichloride, in refluxing CH Cl
2
2
under high dilution conditions resulted in formation
of the lactone 5 in 75% yield after purification
by column chromatography. The spectral data and
specific rotation value of the lactone 5 were in agree-
We wish to report a facile synthesis of (−)-argentilac-
tone 1, starting from the commercially available (S)-
glycidol, that utilizes a ring closing metathesis reaction
as the key step.
4
ment with literature values. Removal of the protecting
group under standard conditions with tetra-n-butylam-
monium flouride in DMF afforded the unsaturated
lactone alcohol 6 in 86% yield. Swern oxidation of 6
provided the unstable aldehyde 7, which was used
directly in the Wittig reaction with hexylidenetri-
phenylphosporane furnishing (−)-argentilactone 1 in
5
0% yield over the two steps. According to the NMR
data and GLC analysis, the diastereomeric ratio of the
olefin formed in the Wittig reaction was >96:4 in favor
of the (Z)-isomer, and the two isomers could be sepa-
rated by column chromatography. The spectral data
and specific rotation value were in good agreement with
*
0
Corresponding author. Fax: +47 22 85 59 47; e-mail: t.v.hansen@
farmasi.uio.no
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00138-6

5
48
T. V. Hansen / Tetrahedron: Asymmetry 13 (2002) 547–550
Scheme 1. (i) TBDPSiCl, imidazole, DMF; (ii) (a) CuCN, THF, −78°C, (b) CH CHMgCl, −78 to −20°C, (c) 2, THF, −78°C; (iii)
2
Et N, acryloyl chloride, THF, 0°C; (iv) RuꢀCHPhCl (PCy ) , CH Cl , D; (v) Bu NF, DMF; (vi) (COCl) , DMSO, Et N, CH Cl ,
3
2
3 2
2
2
4
2
3
2
2
−
78°C; (vii) C H CHꢀPPh , THF, 0°C.
5
11
3
2
5
those published for (−)-argentilactone 1, [h] =−20.5 (c
mL) at 0°C was treated by dropwise addition of a
solution of (S)-glycidol (4.07 g, 55 mmol) in CH Cl (10
D
0
0
.5, EtOH) (as compared to the reported [h] =−21.1 (c
D
2
2
1
.5 EtOH) for natural (−)-argentilactone).
mL) over a period of 20 min. The solution was stirred
for a further 15 h at ambient temperature and the
reaction was worked up in the usual manner. Purifica-
tion by column chromatography (5% EtOAc in hex-
In conclusion, we have reported an efficient seven-step
synthesis of (−)-argentilactone 1 in 22% overall yield.
Our synthetic route compares favorably with those
already published with respect to both overall yield and
2
3
anes) afforded the silyl ether (16.3 g, 95%). [h] =+2.3
D
(c 2.0, CHCl ); IR (film) 2955, 1470, 1110, 825, 700
3
5
−1 1
simplicity.
cm ; H NMR (300 MHz, CDCl ) l 1.08 (s, 9H), 2.65
3
(
3
dd J=5.1, 3.2 Hz, 1H), 2.76 (dd J=5.1, 4.0 Hz, 1H),
.18–3.10 (m, 1H), 3.74 (dd, J=12.0, 4.5 Hz, 1H), 3.85
(
(
dd, J=12.0, 3.2 Hz, 1H), 7.30–7.45 (m, 6H), 7.67–7.73
m, 4H); 19.12, 26.53, 44.25, 52.23, 64.26, 127.61,
3. Experimental
1
27.66, 129.71, 129.78, 133.20, 135.51.
3.1. General
NMR spectra were recorded on a VARIAN MER-
3
.3. (2R)-1-(tert-Butyldiphenylsilyloxy)-4-penten-2-ol 3
1
CURY 300 instrument using CDCl as solvent. H and
3
1
3
C spectra were recorded at 300 and 75 MHz, respec-
CuCN (6.73 g, 75 mmol) was placed in a flask under
argon and dried by gentle heating with a heat gun
under vacuum. After cooling to room temperature,
ether (100 mL) was added and the mixture cooled to
tively. IR spectra were recorded on a Perkin–Elmer
Paragon 500 FT Spectrometer. Analytical GLC was
performed on a 25 M SP2100 capillary column on a
Varian GC 3300 instrument. Optical rotations were
measured on an Optical Activity Ltd. AA-10 Auto-
matic Polarimeter. All reactions were carried out under
an atmosphere of nitrogen. Where the term purified by
column chromatography is used this refers to flash
chromatography using silica gel (230–400 mesh).
−
78°C. The resulting slurry was treated by dropwise
addition of vinylmagnesium chloride (87 mL, 147
mmol) over a period of 15 min. The mixture was
warmed to −20°C until the CuCN dissolved completely,
and then the solution was cooled again to −78°C. A
solution of 2 (10.0 g, 32 mmol) in ether (125 mL) was
added dropwise and the reaction mixture was allowed
to warm to −60°C and stirred for 6 h. The reaction was
quenched by the addition of a saturated solution of
3.2. (R)-(tert-Butyldiphenylsilyloxy)methyloxirane 2
A solution of tert-butyldiphenylsilyl chloride (18.15 g,
NH Cl (50 mL) and warmed to ambient temperature,
the aqueous phase was extracted with ether (2×50 mL),
4
66 mmol) and imidazole (4.5 g, 66 mmol) in DMF (100

T. V. Hansen / Tetrahedron: Asymmetry 13 (2002) 547–550
549
the combined organic solutions were washed with brine
3.6. (R)-Argentilactone 1
and then dried (MgSO ). Removal of the solvents
4
yielded a yellow oil of the alcohol 3 (8.71 g, 80%),
To a stirred solution of oxalyl chloride (0.16 mL, 1.83
mmol) in dry CH Cl (5 mL) was added a solution of
2
3
which was used directly in the next step. [h] =+2.9 (c
D
1 1
2
2
−
0
.9, CHCl ); IR (film) 3078, 2930, 1424 cm ; H NMR
DMSO (2 mL, 2.55 mmol) in dry CH Cl (5 mL) at
3
2 2
(
300 MHz, CDCl ) 1.08 (s, 9H), 2.15 (bs 1H), 2.20–2.25
−78°C. After stirring for 20 min, the alcohol 6 (0.16 g,
3
(
m, 2H), 3.55 (dd, J=10.5, 7.2 Hz, 1H), 3.65 (dd,
1.25 mmol) in dry CH Cl (5 mL) was added dropwise
2
2
J=10.5, 3.5 Hz, 1H), 3.75–3.84 (m, 1H), 5.05–5.12 (m,
H), 5.75–5.82 (m 1H), 7.38–7.44 (m, 6H), 7.66–7.73
and stirring was continued for a further 45 min at this
2
temperature. Et N (0.87 mL, 6.25 mmol) was added
3
1
3
(
m, 4H); C NMR (75 MHz, CDCl ) 19.26, 26.77,
7.54, 67.22, 71.22, 117.42, 127.61, 127.66, 129.71,
29.78, 133.20, 134.37, 135.51.
and stirring was continued for another 30 min. Workup
in the usual manner afforded the aldehyde 7 (126 mg,
80%), which was immediately dissolved in dry THF (5
3
3
1
mL) and added dropwise 5 to
a
solution of
3
.4. (6R)-6-(tert-Butyldiphenylsilyloxy)methyl-5,6-di-
c,11
hexylidenetriphenylphosphorane
in THF (5 mL) at
hydro-2H-pyran-2-one 5
−
15°C. The mixture was then stirred for 45 min. Brine
5 mL) was added followed by the addition of Et O (10
(
2
To a solution of the alcohol (8.5 g, 25 mmol) in dry
THF was added Et N (126 mg, 1.25 mmol) at 0°C. A
mL). The phases were separated and the aqueous phase
3
was extracted with Et O (2×10 mL) and the combined
2
solution of acryloyl acid chloride (2.49 g, 27.5 mmol) in
dry CH Cl (50 mL) was added dropwise to the mixture
over a period of 30 min and stirring was continued for
a further 3 h. Brine (50 mL) was added and the
aqueous phase extracted with ether (2×30 mL), the
combined organic solutions were washed with brine
and then dried (MgSO ). Removal of the solvent
afforded the ester 4 (8.77 g, 89%) which was used as
such in the next step.
organic phases were dried (MgSO ). Evaporation of the
4
2
2
solvent gave a residue which was purified by column
chromatography (EtOAc:hexane, 9:1) to afford (R)-
2
5
argentilactone 1 (132 mg, 62%). [h] =−20.5 (c 0.5
D
EtOH), literature: [h] =−21.1 (c 0.5, EtOH); IR (film)
D
−
1 1
1
730, 1245 cm ; H NMR (300 MHz, CDCl ) 0.89 (t,
3
4
J=7.0 Hz, 3H), 1.25–1.45 (m, 3H), 2.10 (m, 2H), 2.42
(
(
m, 2H), 5.25 (ddd, J=10.0, 8.5, 5.0 Hz, 1H), 5.59
dddd, J=11.0, 8.5, 1.5, 1.0 Hz, 1H), 5.68 (dtd, J=
1
1
1.0, 7.5, 0.7 Hz, 1H), 6.06 (ddd, J=10.0, 2.5, 1.5 Hz,
H), 6.92 (ddd, J=10.0, 5.2, 3.1, 1H); C NMR (75
Grubb’s catalyst (0.16 g, 0.02 mmol, 10 mol%) was
13
dissolved in dry CH Cl (5 mL) and was added drop-
2
2
MHz, CDCl ) 14.06, 22.47, 27.75, 29.08, 29.88, 31.41,
3
wise to a refluxing solution of the above ester 4 (0.79 g,
mmol) in dry CH Cl (200 mL). The mixture was
7
3.94, 121.53, 126.40, 135.66, 144.92, 164.28.
2
2
2
heated under reflux for 6 h by which time all of the
starting material was consumed (TLC). The solvent was
removed and the reaction mixture was purified by
column chromatography (25% EtOAc in hexane) to
Acknowledgements
2
3
obtain 5 as an oil (0.55 g, 75%). [h] =+34.2 (c 1.5,
D
Financial support from the Norwegian Research Coun-
cil is gratefully acknowledged.
−
1 1
CHCl ); IR (film) 3078, 2930, 1424 cm ; H NMR (300
3
MHz, CDCl ) 1.08 (s, 9H), 2.45 (dddd, 18.5, 5.5, 4.5,
3
1
1
1
.1 Hz, 1H), 2.60 (dddd, 18.5 Hz, 11.0, 9.5, 2.5, 2.5 Hz,
H), 3.85 (d, J=5.0 Hz, 2H), 3.65 (dd, J=10.5, 3.5 Hz,
H), 4.50 (dddd, J=11.0 Hz, 9.5, 5.0, 5.0 Hz, 1H), 6.05
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6
1
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2
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1
0
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−
1
colorless oil (0.16 g, 86%). IR (film) 1732, 3350 cm ;
1
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3
2
6
1
+
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.06 (dd, J=10.0, 3.5, Hz, 1H), 6.96 (ddd, J=10.0, 3.5,
2
2
26
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D
3
D
174.95 (c 0.92, CHCl3); HRMS (m/z). Found
28.0466, calculated 128.0472 for C H O (M ).
+
1
6 8 3

5
50
T. V. Hansen / Tetrahedron: Asymmetry 13 (2002) 547–550
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4
04.