Stereoselective Synthesis of Stagonolide G from d -Mannitol

Article abstract of DOI:10.1055/s-0030-1258389

A highly convergent, stereoselective total synthesis of a ten-membered lactone, stagonolide G, is described. Epoxide ring-opening with vinyl Grignard, Yamaguchi esterification and ring-closing metathesis are the key steps involved in the present approach.

Full text of DOI:10.1055/s-0030-1258389

PAPER
451
Stereoselective Synthesis of Stagonolide G from D-Mannitol
Stereoselective
S
h
S
e
tagonolide
b
Gfrom
D
-M
o
annitol lu Naga Sesha Sai Pavan Kumar, Mettu Ravinder, Singam Naveen Kumar, Vaidya Jayathirtha Rao*
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
Fax +91(40)27160757; E-mail: jrao@iict.res.in
Received 15 October 2010; revised 29 November 2010
yield.7 Protection of the alcohol using p-methoxybenzyl
chloride (PMBCl) and sodium hydride produced the cor-
responding ether 14, which, after subsequent cyclohexy-
lidene deprotection with 1 M HCl, gave the diol 15.
Abstract: A highly convergent, stereoselective total synthesis of a
ten-membered lactone, stagonolide G, is described. Epoxide ring-
opening with vinyl Grignard, Yamaguchi esterification and ring-
closing metathesis are the key steps involved in the present ap-
proach. D-Mannitol was used as a chiral pool material for the con- Selective tosylation of diol 15 with tosyl chloride8 using
struction of both of the key fragments – the olefinic acid and the
triethylamine and a catalytic amount of dibutyltin oxide
olefinic alcohol moieties.
(Bu2SnO) at 0 °C, followed by treatment with potassium
carbonate in methanol, provided epoxide 16.9 The crucial
Key words: chiral pool, Grignard reaction, esterification, ring clo-
sure, macrocycles
regioselective ring-opening of the epoxide to allyl alcohol
17 was achieved10 by treatment of 16 with vinylmagne-
sium bromide and copper(I) iodide at –20 °C (Scheme 2).
Macrolides, particularly lactones with medium-sized Silylation of allylic alcohol 17 with tert-butyldimethylsi-
rings (8–10 membered), have continued to attract the at-
tention of both biologists and chemists during recent
OH
OH
O
OH
years, due to their interesting biological properties1 and
scarce availability. Ten-membered ring lactones noneno-
lides, stagonolides B–I (1–8) and modiolide A (9) are re-
cent examples (Figure 1) that have been isolated in both
liquid and solid cultures of Stagonospora cirsii Davis,
which is a fungal pathogen isolated from Cirsium ar-
vense.2 In accordance with our continuing synthetic
efforts3 towards molecules with intriguing characteristics
and usefulness, recently we reported the synthesis and
bioevaluation of stagonolide F.3c
OH
OH
H
OH
O
O
O
O
H
O
O
stagonolide B (1)
stagonolide C (2)
stagonolide D (3)
OH
OH
OH
O
O
OH
O
O
O
O
Herein, we report a simple and efficient approach to the
total synthesis of stagonolide G (6), starting from the in-
expensive and easily available starting material, D-manni-
tol. During the course of our study, Yadav et al.4 reported
the first total synthesis of stagonolide G using D-glucose
diacetonide and 1,4-butanediol as starting materials.
stagonolide E (4)
stagonolide F (5)
stagonolide G (6)
OH
OH
HO
H
O
H
OH
OH
O
O
O
Our retrosynthetic strategy for stagonolide G is depicted
in Scheme 1. The analysis revealed that 6 could be pre-
pared efficiently by a ring-closing metathesis (RCM) pro-
tocol from bis-olefin 28, which, in turn, could be prepared
by Yamaguchi esterification of acid 20 and vinyl alcohol
25. Fragments 20 and 25 were both envisaged to be ob-
tained from cyclohexylidene-D-glyceraldehydes, which
could be obtained easily from D-mannitol.
O
O
O
stagonolide H (7)
stagonolide I (8)
modiolide A (9)
Figure 1 Phytotoxic nonenolides.
OH
O
OH
O
O
OBn
OH
Accordingly, our synthesis began with 2,3-O-cyclohexyl-
idene-D-glyceraldehyde (10), which was readily obtained
from D-mannitol.5 C2-Wittig olefination under Masamune–
Roush conditions gave unsaturated ester 11.6 Hydrogena-
tion of the latter with Pd/C, followed by lithium aluminum
hydride mediated reduction, afforded alcohol 13 in high
O
6
28
OH
OTBS
+
HOOC
OBn
20
25
SYNTHESIS 2011, No. 3, pp 0451–0458
Advanced online publication: 05.01.2011
x
x
.
x
x
.2
0
1
1
D-mannitol
DOI: 10.1055/s-0030-1258389; Art ID: T20710SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthesis of stagonolide G

452
C. N. S. S. Pavan Kumar et al.
PAPER
25
lyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine for the anti compound, observed: [a]D +39.6 (c 0.6,
25
afforded the corresponding ether 18, which was subjected CHCl3), reported: [a]D +46.6 (c 0.81, CHCl3)}.14 The
to selective PMB deprotection with 2,3-dichloro-5,6-di- anti isomer was subjected to debenzylation, followed by
cyano-1,4-benzoquinone (DDQ) in dichloromethane/wa- Mitsunobu reaction, to furnish the desired syn product.
ter to give 19. Finally, oxidation of alcohol 19 either with Cyclohexylidene cleavage of the syn compound 22b led to
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/bis(ace- the formation of diol 23. Subsequent selective tosylation
toxy)iodobenzene (BAIB)11 or with pyridinium dichro- of the primary hydroxy group 23 with tosyl chloride, tri-
mate (PDC)/N,N-dimethylformamide12 provided the ethylamine and a catalytic amount of Bu2SnO produced
desired acid fragment 20 in 80% yield (Scheme 2).
the corresponding tosylate, which, on treatment with po-
tassium carbonate in methanol, gave epoxide 24.9c Final-
ly, epoxide ring-opening with lithium aluminum hydride
in anhydrous tetrahydrofuran afforded alcohol fragment
25 in 84% yield.15
O
ref. 5
a
O
D-mannitol
O
OEt
90%
O
O
Condensation of fragments 20 and 25 was achieved under
Yamaguchi conditions16 to furnish bis-olefinic ester 26 in
80% yield (Scheme 4). Initial attempts at ring-closing
metathesis of 26 under typical conditions were problemat-
ic.
O
11
10
O
O
c
b
95%
O
OEt
O
OR
d
85%
13 R = H
12
O
84%
a
14 R = PMB
ref 13
O
O
O
84%
O
O
O
OH
O
e
f
OH
21
14
OPMB
OPMB
HO
OPMB
75%
10
80%
15
16
O
O
+
OTBS
OH
h
O
g
OPMB
95%
80%
OBn
HO
OBn
22b
18
17
separable
OH
22a
OTBS
OTBS
j
b
i
c
22b
OH
COOH
80%
75%
80%
85%
OBn
20
19
23
OH
Scheme 2 Reagents and conditions: (a) (OEt)2P(O)CH2COOEt,
LiCl, DIPEA, MeCN, r.t.; (b) Pd/C, H2, EtOAc, r.t.; (c) LAH, THF,
0 °C→r.t.; (d) NaH, PMBCl, anhyd DMF, 0 °C→r.t.; (e) 1 M HCl,
MeCN, r.t.; (f) (i) TsCl, Et3N, nBu2SnO, CH2Cl2, 0 °C→r.t.; (ii)
K2CO3, MeOH, 0 °C→r.t.; (g) CH2=CH-MgBr, CuI, anhyd THF,
–20 °C; (h) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (i) DDQ,
CH2Cl2/H2O (10:1), 0 °C→r.t.; (j) TEMPO, BAIB, MeCN–H2O
(1:1), r.t. or PDC, DMF, r.t.
O
d
84%
OBn
OBn
24
25
Scheme 3 Reagents and conditions: (a) NaH, BnBr, anhyd THF,
0 °C→r.t.; (b) 1 M HCl, MeCN, r.t.; (c) (i) TsCl, Et3N, nBu2SnO,
CH2Cl2, 0 °C→r.t.; (ii) K2CO3, MeOH, 0 °C→r.t.; (d) LiAlH4, anhyd
THF, 0 °C→r.t.
The synthesis of alcohol fragment 25 is summarized in
Scheme 3. In this regard, 2,3-O-cyclohexylidene-D-glyc-
eraldehyde was treated with vinylmagnesium bromide to
give 21 as an almost inseparable 1:1 diastereomeric
mixture13 (from GC-MS analysis); the free hydroxy group
in the mixture of 21 was protected as the corresponding
ethers by treatment with benzyl bromide to give com-
pounds 22a and 22b, which were separated by silica gel
column chromatography.14 For the assignment of syn and
anti configurations, a small amount of the two compounds
22a/22b were subjected to cyclohexylidene deprotection
separately and the resulting syn and anti alcohols were
compared with the reported spectral and rotation values
After numerous conditions were tried with Grubbs I and
Grubbs II catalysts in a range of traditional solvents for
metathesis (CH2Cl2, benzene, or toluene), the final out-
come was the same in all cases. Either inseparable mix-
tures of various compounds (along with a small amount of
product 27) were obtained or the starting material decom-
posed during the course of the reaction. Gratifyingly, after
desilylation of 26 under neutral conditions with HF·pyri-
dine and subsequent olefin metathesis using Grubbs II cat-
alyst (20 mol%) in refluxing anhydrous dichloromethane
under high dilution conditions,17 the desired lactone 29
1
was furnished exclusively in the Z form.18 The H NMR
25
{optical rotation of the syn compound, observed: [a]D
shift values at d = 5.4–5.7 ppm in the crude spectrum with
–34.4 (c 1,CHCl3), reported: [a]D25 –40.6 (c 0.47, CHCl3);
a coupling constant JH-6 H-7 = 11.3 Hz, allowed the Z-ste-
,
Synthesis 2011, No. 3, 451–458 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Stagonolide G from D-Mannitol
453
an Agilent 6890 series (column: Varian CP-Sil 8 CB, 5% phenyl,
95% PDMS, 30.0 m × 250 mm × 0.30 mm nominal).
reochemistry to be assigned for 29. Finally, deprotection
of the benzyl moiety with sodium and liquid ammonia un-
der Birch conditions19 afforded the target molecule 6
(Scheme 4). The physical and spectral data of 6 were
identical to those reported in the literature.2b,4
(S,E)-Ethyl 3-(1,4-Dioxaspiro[4.5]decan-2-yl)acrylate (11)7
To a well-stirred solution of anhydrous LiCl (0.98 g, 23.3 mmol) in
anhydrous MeCN (15 mL) under nitrogen were sequentially added
triethyl phosphonoacetate (5.21 g, 23.3 mmol), DIPEA (3.01 g, 23.3
mmol) and freshly prepared aldehyde 10 (3.3 g, 19.4 mmol) at r.t.,
and the mixture was stirred for 24 h at the same temperature. The
reaction was diluted with H2O (15 mL), extracted with EtOAc
(3 × 10 mL) and the combined organic layers were washed with
brine (20 mL), dried over Na2SO4, filtered and concentrated to give
an oily residue that was subjected to silica gel column chromatog-
raphy (60–120 mesh; EtOAc–hexane, 1:49) to give separable E-iso-
mer (4.01 g, 86.4%) and Z-isomer (0.16 g, 3.5%) as a colorless oils.
OTBS
OTBS
a
20 + 25
O
O
O
80%
OBn
OBn
O
26
27
b
78%
E-Isomer
OH
25
OH
O
Rf = 0.8 (silica gel; EtOAc–hexane, 2:8); [a]D +32.1 (c 1.4,
MeOH).
IR (neat): 2937, 2861, 1722, 1660, 1302, 1267 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.32 (t, J = 7.5 Hz, 3 H, CH3),
1.41–1.63 (m, 10 H, Cy-H), 3.65 (t, J = 7.5 Hz, 1 H, OCH2), 4.08–
4.22 (m, 3 H, CH2CO2, OCH2), 4.65 (dd, J = 6.7, 1.5 Hz, 1 H,
OCH), 6.08 (d, J = 16.6 Hz, 1 H, =CH), 6.87 (dd, J = 6.0, 15.8 Hz,
1 H, =CH).
c
O
65%
O
OBn
OBn
O
28
29
68%
d
13C NMR (50 MHz, CDCl3): d = 14.1 (CH3), 23.7 (Cy), 23.8 (Cy),
24.9 (Cy), 35.1 (Cy), 35.9 (Cy), 60.4 (OCH2CH3), 68.3 (CH2O),
74.5 (CH), 110.6 (C), 122.1 (=CH), 144.8 (=CH), 165.8 (CO).
OH
MS (ESI): m/z = 263 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H20O4Na: 263.1259;
O
OH
O
found: 263.1262.
6
(S)-Ethyl 3-(1,4-Dioxaspiro[4.5]decan-2-yl)propanoate (12)7
A solution of the unsaturated ester 11 (1.0 g, 3.33 mmol) in EtOAc
(8 mL) was stirred magnetically in the presence of 10% Pd/C as cat-
alyst in an atmosphere of hydrogen for 6 h. The catalyst was filtered
off and the solvent was removed under reduced pressure to afford
the ester 12.
Scheme 4 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl
chloride, Et3N, anhyd THF, r.t., 2 h, DMAP, toluene, r.t.; (b) HF·py-
ridine, anhyd THF, 0 °C→r.t.; (c) Grubbs II catalyst, anhyd CH2Cl2,
reflux; (d) Na, liq NH3, anhyd THF, –78 °C.
In conclusion, we have developed a simple, convenient
and economic route for the stereoselective synthesis of
stagonolide G by employing D-mannitol as a chiral tem-
plate. This protocol involves the use of a Grignard reac-
tion and ring-closing metathesis as key steps. The
syntheses of other related compounds of this family are
underway in our laboratory.
Yield: 0.95 g (95%); colorless liquid; Rf = 0.7 (silica gel; EtOAc–
hexane, 2:8); [a]D25 –3.1 (c 1.1, CHCl3).
IR (neat): 2936, 2861, 1735, 1447, 1368, 1105, 1037, 930 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 6.0 Hz, 3 H, CH3),
1.43–1.63 (m, 10 H, Cy-H), 1.70–1.93 (m, 2 H, CH2), 2.28–2.47
(m, 2 H, COCH2), 3.49 (t, J = 7.5 Hz, 1 H, OCH), 3.87–4.17 (m,
4 H, 2 × OCH2).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 23.6 (Cy), 23.8 (Cy),
24.9 (Cy), 28.7 (CH2), 30.3 (CH2CO), 34.9 (Cy), 36.4 (Cy), 60.2
(OCH2CH3), 68.5 (CH2O), 74.3 (CH), 109.3 (C), 173.0 (CO).
MS (ESI): m/z = 243 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H23O4: 243.1490; found:
All reactions were carried out under an inert atmosphere unless
mentioned otherwise, and standard syringe–septa techniques were
followed. Solvents were freshly dried and purified by conventional
methods prior to use. The progress of all the reactions were moni-
tored by TLC, using TLC aluminum-backed sheets precoated with
silica gel 60 F254 to a thickness of 0.25 mm (Merck). Column chro-
matography was performed on silica gel (60–120 mesh and 100–
200 mesh), and Et2O, EtOAc, and hexane were used as eluents. Op-
tical rotation values were measured with a Perkin–Elmer P241 po-
larimeter and a JASCO DIP-360 digital polarimeter, and IR spectra
243.1484.
(S)-3-(1,4-Dioxaspiro[4.5]decan-2-yl)propan-1-ol (13)7
To a suspension of LAH (0.45 g, 12.39 mmol) in anhydrous THF
(20 mL) was added ester 12 (3.0 g, 12.39 mmol) in anhydrous THF
(10 mL) at 0 °C under a nitrogen atmosphere and the mixture was
stirred at r.t. for 2 h. The reaction mixture was quenched with sat.
aq NH4Cl (10 mL), filtered, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by silica gel
column chromatography (60–120 mesh; EtOAc–hexane, 2:8) to af-
ford 13.
1
were recorded with a Perkin–Elmer FT-IR spectrophotometer. H
and 13C NMR spectra were recorded with Varian Gemini 200 MHz,
Bruker Avance 300 MHz, Varian Unity 400 MHz, or Varian Inova
500 MHz spectrometers; TMS was used as an internal standard in
CDCl3. Mass spectra were recorded with a VG Micromass 7070 H
(EI), QSTAR XL high-resolution mass spectrometer, a Thermo
Finnigan ESI ion trap Mass Spectrometer and a GC-MS system on
Yield: 2.1 g (85%); colorless liquid; Rf = 0.3 (silica gel; EtOAc–
hexane, 3:7); [a]D25 +6.6 (c 0.95, CHCl3).
Synthesis 2011, No. 3, 451–458 © Thieme Stuttgart · New York

454
C. N. S. S. Pavan Kumar et al.
PAPER
IR (neat): 3423, 2935, 2861, 1637, 1446, 1103, 930 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C13H20O4Na: 263.1259;
found: 263.1254.
1H NMR (300 MHz, CDCl3): d = 1.35–1.43 (m, 2 H, CH2), 1.53–
1.71 (m, 12 H, Cy-H, CH2), 2.25 (br s, 1 H, OH), 3.47 (t, J = 7.5 Hz,
1 H, OCH), 3.59–3.68 (m, 2 H, CH2OH), 3.98–4.03 (m, 1 H, OCH),
4.04–4.12 (m, 1 H, OCH).
13C NMR (75 MHz, CDCl3): d = 23.8 (Cy), 23.9 (Cy), 25.0 (Cy),
29.2 (CH2), 30.4 (CH2), 35.1 (Cy), 36.4 (Cy), 62.5 (CH2OH), 69.1
(CH2O), 75.5 (CH), 109.5 (C).
(S)-2-[3-(4-Methoxybenzyloxy)propyl]oxirane (16)
To an ice-cold solution of diol 15 (2.5 g, 10.4 mmol), a catalytic
amount of dibutyl tin oxide (0.5 g, 2 mmol) and Et3N (1.6 mL, 12.0
mmol) in anhydrous CH2Cl2 (30 mL) were added. After 15 min at
r.t., the reaction mixture was cooled to 0 °C then TsCl (2.3 g, 12.0
mmol) was added portion-wise and the reaction was stirred at r.t. for
4 h. After completion of reaction, the mixture was diluted with H2O
(5 mL) and extracted into CH2Cl2 (3 × 50 mL). The organic layer
was washed with brine (2 × 25 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure to give the crude residue.
This residue was dissolved in MeOH (10 mL) and anhydrous
K2CO3 (1.68 g, 12.1 mmol) was added at 0 °C. The mixture was
stirred at r.t. for 3 h. After dilution with EtOAc (20 mL), the organic
layer was washed with H2O (2 × 10 mL) and brine (25 mL). Drying,
followed by evaporation and purification by silica gel column chro-
matography (60–120 mesh; EtOAc–hexane, 1:24) afforded 16.
MS (ESI): m/z = 201 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H21O3: 201.1490; found:
201.1484.
(S)-2-[3-(4-Methoxybenzyloxy)propyl]-1,4-dioxaspiro[4.5]dec-
ane (14)
To a suspension of NaH (0.72 g, 30.0 mmol) in anhydrous DMF (10
mL) was added alcohol 13 (3.0 g, 15.0 mmol) in DMF (10 mL) at
0 °C and the mixture was stirred for 30 min. p-Methoxybenzyl chlo-
ride (PMBCl; 2.2 mL, 16.5 mmol) was added and the mixture was
stirred for 8 h. The reaction was quenched with cold H2O (10 mL)
and then extracted with Et2O (3 × 20 mL), and the combined organ-
ic layers were washed with brine (25 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The crude residue was purified by
silica gel column chromatography (60–120 mesh; EtOAc–hexane,
1:24) to afford 14.
Yield: 75%; colorless oil; Rf = 0.7 (silica gel; EtOAc–hexane, 3:7);
[a]D25 –4.5 (c 0.88, CHCl3).
IR (neat): 2933, 2856, 1612, 1512, 1246, 1094, 1033, 821 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.47–1.81 (m, 4 H, 2 × CH2), 2.38
(dd, J = 2.6, 5.1 Hz, 1 H, oxirane-H), 2.68 (t, J = 4.9 Hz, 1 H,
oxirane-H), 2.83–2.89 (m, 1 H, oxirane-H), 3.38–3.49 (m, 2 H,
OCH2), 3.78 (s, 3 H, OCH3), 4.39 (s, 2 H, CH2Ar), 6.81 (d,
J = 8.4 Hz, 2 H, ArH), 7.18 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.1 (CH2), 29.2 (CH2), 46.9
(oxirane-CH2), 51.9 (oxirane-CH), 55.1 (OCH3), 69.3 (CH2O), 72.4
(CH2Ar), 113.6 (2 × CAr), 129.1 (2 × CAr), 130.4 (CAr), 159.0 (CAr).
Yield: 4.0 g (84%); colorless liquid; Rf = 0.8 (silica gel; EtOAc–
hexane, 2:8); [a]D25 +4.5 (c 1, CHCl3).
IR (neat): 2935, 2857, 1613, 1512, 1246, 1097, 1035, 931, 819 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33–1.45 (m, 4 H, 2 × CH2),
1.49–1.68 (m, 10 H, Cy-H), 3.37–3.50 (m, 3 H, OCH2, OCH), 3.78
(s, 3 H, OCH3), 3.94–4.07 (m, 2 H, OCH2), 4.38 (s, 2 H, CH2Ar),
6.81 (d, J = 8.6 Hz, 2 H, ArH), 7.18 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 23.9 (Cy), 24.0 (Cy), 25.3 (CH2),
26.1 (Cy), 30.5 (CH2), 35.3 (Cy), 36.7 (Cy), 55.0 (OCH3), 69.0
(CH2O), 69.6 (CH2O), 72.5 (CH), 75.3 (CH2Ar), 109.1 (C), 113.7
(2 × CAr), 129.1 (2 × CAr), 130.5 (CAr), 159.1 (CAr).
MS (ESI): m/z = 240 [M + NH4]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H18O3Na: 245.1153;
found: 245.1147.
(S)-7-(4-Methoxybenzyloxy)hept-1-en-4-ol (17)
A solution of vinylmagnesium bromide (1 M in THF, 18 mL, 18
mmol; Aldrich) in THF (10 mL) was quickly added to a solution of
epoxide 16 (1.0 g, 4.5 mmol) in anhydrous THF (10 mL) and fresh-
ly flame-dried CuI (0.85 g, 4.5 mmol) at –20 °C. The progress of the
reaction was monitored by TLC. After completion (1 h), sat. aq
NH4Cl (5 mL) was added, the organic layer was washed with brine
(20 mL), dried over Na2SO4 and concentrated under reduced pres-
sure to give the crude residue, which was purified by silica gel col-
umn chromatography (60–120 mesh; EtOAc–hexane, 1:9) to afford
17.
MS (ESI): m/z = 321 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H28O4Na: 343.1885;
found: 343.1898.
(S)-5-(4-Methoxybenzyloxy)pentane-1,2-diol (15)
To a solution of 14 (3.0 g, 12.5 mmol) in MeCN (45 mL) was added
HCl (1 M, 36 mL) and the mixture was stirred at r.t. for 3 h. After
completion of the reaction, the contents were neutralized with solid
NaHCO3 and the solvent was removed. The residue was diluted
with H2O (30 mL) and extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and the sol-
vent was removed under reduced pressure to obtain the crude
product, which was purified by silica gel column chromatography
(60–120 mesh; EtOAc–hexane, 1:1) to afford 15.
Yield: 0.9 g (80%); colorless oil; Rf = 0.3 (silica gel; EtOAc–
hexane, 2:8); [a]D25 –9.1 (c 0.92, CHCl3).
IR (neat): 3422, 3072, 2927, 2856, 1612, 1512, 1246, 1090, 1033,
819 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41–1.49 (m, 1 H, CH2), 1.58–
1.66 (m, 1 H, CH2), 1.67–1.76 (m, 2 H, CH2), 2.11–2.26 (m, 2 H,
CH2C=), 2.33 (br s, 1 H, OH), 3.44 (t, J = 5.7 Hz, 2 H, OCH2),
3.56–3.63 (m, 1 H, CHOH), 3.78 (s, 3 H, OCH3), 4.41 (s, 2 H,
CH2Ar), 5.06 (s, 1 H, =CH), 5.09 (d, J = 4.8 Hz, 1 H, =CH), 5.75–
5.84 (m, 1 H, =CH), 6.81 (d, J = 8.6 Hz, 2 H, ArH), 7.19 (d,
J = 8.6 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.1 (CH2), 33.9 (CH2), 41.8
(CH2), 55.1 (OCH3), 70.0 (CH), 70.5 (CH2O), 72.5 (CH2O), 113.7
(2 × CAr), 117.5 (=CH2), 129.2 (2 × CAr), 130.1 (CAr), 135.0 (=CH),
159.1 (CAr).
Yield: 1.8 g (80%); colorless oil; Rf = 0.2 (silica gel; EtOAc–
hexane, 1:1); [a]D25 –2.0 (c 1.1, CHCl3).
IR (neat): 3402, 2934, 2862, 1612, 1512, 1246, 1080, 1033, 819
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40–1.63 (m, 2 H, CH2), 1.67–
1.78 (m, 2 H, CH2), 3.34–3.69 (m, 5 H, 2 × OCH2, OCH), 3.79 (s,
3 H, OCH3), 4.42 (s, 2 H, CH2Ar), 6.82 (d, J = 8.4 Hz, 2 H, ArH),
7.18 (d, J = 8.6 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.1 (CH2), 30.7 (CH2), 55.2
(OCH3), 66.7 (CH2OH), 70.1 (CHOH), 71.9 (CH2O), 72.7 (CH2Ar),
113.8 (2 × CAr), 129.3 (2 × CAr), 129.8 (CAr), 159.2 (CAr).
MS (ESI): m/z = 251 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22O3Na: 273.1466;
MS (ESI): m/z = 241 [M + H]+.
found: 273.1455.
Synthesis 2011, No. 3, 451–458 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Stagonolide G from D-Mannitol
455
[(S)-7-(4-Methoxybenzyloxy)hept-1-en-4-yloxy](tert-butyl)di-
methylsilane (18)
combined organic extracts were washed with aq NaHCO3 (5 mL)
and brine (15 mL), dried (Na2SO4), and concentrated under reduced
pressure. Flash column chromatography over silica gel (60–120
mesh; EtOAc–hexane, 1:5) afforded pure acid 20 (0.42 g, 80%) as
a colorless liquid.
To a stirred solution of alcohol 17 (1.0 g, 4.0 mmol) in CH2Cl2 (10
mL), 2,6-lutidine (1.39 mL, 12 mmol) and TBSOTf (1.37 mL, 6
mmol) were added sequentially at 0 °C, under a nitrogen atmo-
sphere. The reaction mixture was stirred from 0 °C to r.t. for 15 min
and then quenched by addition of sat. aq NaHCO3 (5 mL). The re-
sulting mixture was extracted with EtOAc (2 × 15 mL) and the or-
ganic extracts were washed with sat. aq CuSO4 (2 × 5 mL), H2O (10
mL), and brine (20 mL), dried (Na2SO4), filtered and concentrated
under reduced pressure. Purification by silica gel column chroma-
tography (60–120 mesh; EtOAc–hexane, 1:24) furnished com-
pound 18.
Method 2: To a stirred solution of 19 (0.5 g, 2.0 mmol) in DMF (20
mL) was added PDC (3.76 g, 10 mmol) at r.t. After 10 h, the mix-
ture was quenched with cold H2O (15 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic layer was washed with
KHSO4 (15 mL, 1 mol/L), H2O (10 mL), and brine (10 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Flash chromatography of the residue over silica gel afforded 20 as
a colorless liquid (0.39 g, 75%).
Yield: 1.3 g (95%); colorless liquid; Rf = 0.9 (silica gel; EtOAc–
hexane, 1:9); [a]D25 –10.8 (c 1, CHCl3).
25
Rf = 0.2 (silica gel; EtOAc–hexane, 3:7); [a]D –28.2 (c 0.75,
CHCl3).
IR (neat): 3073, 2932, 2856, 1612, 1513, 1249, 1094, 1040, 833,
774 cm–1.
IR (neat): 3076, 2932, 2858, 1710, 1254, 1087, 836, 775 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.05 [s, 6 H, Si(CH3)2], 0.89 [s,
9 H, C(CH3)3], 1.65–1.88 (m, 2 H, CH2), 2.19–2.26 (m, 2 H,
CH2C=), 2.37–2.45 (m, 2 H, CH2CO2), 3.72–3.82 (m, 1 H, OCH),
5.0–5.11 (m, 2 H, 2 × =CH), 5.69–5.86 (m, 1 H, =CH).
13C NMR (75 MHz, CDCl3): d = –4.7 (SiCH3), –4.3 (SiCH3), 18.0
[C(CH3)3], 25.8 (3 × CH3), 29.8 (CH2), 31.1 (CH2), 41.7 (CH2), 70.6
(CH), 117.2 (=CH2), 134.5 (=CH), 180.1 (COOH).
1H NMR (300 MHz, CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.87 [s,
9 H, C(CH3)3], 1.39–1.69 (m, 4 H, 2 × CH2), 2.18 (t, J = 6.2 Hz,
2 H, CH2C=), 3.37 (t, J = 6.2 Hz, 2 H, OCH2), 3.63–3.73 (m, 1 H,
OCH), 3.78 (s, 3 H, OCH3), 4.38 (s, 2 H, CH2Ar), 4.97 (s, 1 H,
=CH), 4.99–5.04 (m, 1 H, =CH), 5.67–5.84 (m, 1 H, =CH), 6.80 (d,
J = 8.3 Hz, 2 H, ArH), 7.18 (d, J = 8.3 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = –4.5 (SiCH3), –4.3 (SiCH3), 18.1
[C(CH3)3], 25.6 (3 × CH3), 25.8 (CH2), 33.2 (CH2), 41.9 (CH2), 55.2
(OCH3), 70.2 (CH2O), 71.7 (CH), 72.4 (CH2O), 113.6 (2 × CAr),
116.6 (=CH2), 129.1 (2 × CAr), 130.6 (CAr), 135.2 (=CH), 159.0
(CAr).
MS (ESI): m/z = 259 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H26O3NaSi: 281.1548;
found: 281.1552.
(R)-2-[(R)-1-(Benzyloxy)allyl]-1,4-dioxaspiro[4.5]decane (22)14
Anhydrous THF (10 mL) was added to a 60% dispersion of NaH in
mineral oil (0.9 g, 37.8 mmol). The flask was cooled in an ice bath,
21 (3.0 g, 15.1 mmol) dissolved in anhydrous THF (20 mL) was
added dropwise and the mixture was stirred for 30 min. Benzyl bro-
mide (2.1 mL, 18.1 mmol) was added and the reaction mixture was
stirred overnight and quenched by the careful addition of a few mil-
liliters of cold H2O. The solvent was then evaporated under reduced
pressure to yield two separable diastereomers (84% yields), which
were separated by silica gel chromatography (100–200 mesh;
EtOAc–hexane, 1:99) to give 22a and 22b.
MS (ESI): m/z = 365 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H36O3NaSi: 387.2331;
found: 387.2331.
(S)-4-(tert-Butyldimethylsilyloxy)hept-6-en-1-ol (19)
To a stirred solution of 18 (0.5 g, 1.37 mmol) in CH2Cl2–H2O (10:1,
15 mL), DDQ (0.37 g, 1.6 mmol) was added at 0 °C and the mixture
was stirred at r.t. for 2 h. Sat. aq NaHCO3 (5 mL) was added to the
reaction mixture and extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic layers were washed with H2O (5 mL), brine (5 mL),
dried over Na2SO4, and concentrated. The crude residue was puri-
fied by silica gel column chromatography (60–120 mesh; EtOAc–
hexane, 1:49) to afford 19.
Data for 22b
25
Rf = 0.9 (silica gel; EtOAc–hexane, 1:9), [a]D –12.4 (c 0.7,
CHCl3).
Yield: 0.28 g (85%); colorless syrup; Rf = 0.5 (silica gel; EtOAc–
hexane, 1:9); [a]D25 –5.6 (c 0.8, CHCl3).
IR (neat): 2934, 2859, 1632, 1447, 1103, 928, 698 cm–1.
IR (neat): 3358, 3077, 2932, 2859, 1640, 1435, 1253, 1054, 834,
773 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39 (m, 2 H, Cy-H), 1.50–1.63
(m, 8 H, Cy-H), 3.70 (q, J = 6.0 Hz, 1 H, OCH), 3.80 (t, J = 6.8 Hz,
1 H, OCH), 3.88 (q, J = 6.0 Hz, 1 H, OCH), 4.15 (q, J = 6.8 Hz,
1 H, OCH), 4.44 (d, J = 12.8 Hz, 1 H, CH2Ar), 4.66 (d, J = 12.8 Hz,
1 H, CH2Ar), 5.27–5.35 (m, 2 H, 2 × =CH), 5.65–5.79 (m, 1 H,
=CH), 7.21–7.34 (m, 5 H, ArH).
1H NMR (300 MHz, CDCl3): d = 0.05 [s, 6 H, Si(CH3)2], 0.89 [s,
9 H, C(CH3)3], 1.46–1.67 (m, 4 H, 2 × CH2), 2.23 (t, J = 6.7 Hz,
2 H, CH2C=), 3.54–3.65 (m, 2 H, CH2OH), 3.69–3.80 (m, 1 H,
OCH), 4.99 (s, 1 H, =CH), 5.03 (d, J = 5.8 Hz, 1 H, =CH), 5.67–
5.82 (m, 1 H, =CH).
13C NMR (75 MHz, CDCl3): d = –4.5 (SiCH3), –4.4 (SiCH3), 18.1
[C(CH3)3], 25.8 (3 × CH3), 28.2 (CH2), 33.0 (CH2), 41.4 (CH2), 63.1
(CH2OH), 71.7 (CH), 116.9 (=CH2), 135.0 (=CH).
13C NMR (75 MHz, CDCl3): d = 23.7 (Cy), 23.8 (Cy), 25.0 (Cy),
34.7 (Cy), 36.0 (Cy), 65.2 (CH2O), 70.1 (CH2Ar), 76.9 (CH), 80.9
(CH), 110.1 (C), 119.8 (=CH2), 127.3 (2 × CAr), 127.6 (CAr), 128.1
(2 × CAr), 134.1 (=CH), 138.2 (CAr).
MS (ESI): m/z = 245 [M + H]+.
MS (ESI): m/z = 306 [M + NH4]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H28O2NaSi: 267.1756;
HRMS (ESI): m/z [M + Na]+ calcd for C18H24O3Na: 311.1623;
found: 267.1756.
found: 311.1621.
(S)-4-(tert-Butyldimethylsilyloxy)hept-6-enoic Acid (20)
(2R,3R)-3-(Benzyloxy)pent-4-ene-1,2-diol (23)14
Method 1: BAIB (1.9 g, 6 mmol) was added to a solution of alcohol
19 (0.5 g, 2 mmol) and TEMPO (95 mg, 0.3 mmol) in MeCN–H2O
(1:1, 10 mL). The reaction mixture was stirred for 2 h at r.t., and
then diluted with CH2Cl2 (10 mL). The mixture was washed with
sat. aq Na2S2O3 (5 mL) and extracted with CH2Cl2 (3 × 15 mL). The
To a solution of 22b (2.0 g, 6.9 mmol) in MeCN (30 mL) was added
HCl (1 M, 24 mL) and the mixture was stirred at r.t. for 3 h. After
completion of the reaction, the contents were neutralized with solid
NaHCO3 and the solvent was removed. The residue was diluted
with H2O (30 mL) and extracted with EtOAc (3 × 50 mL). The com-
Synthesis 2011, No. 3, 451–458 © Thieme Stuttgart · New York

456
C. N. S. S. Pavan Kumar et al.
PAPER
bined organic layers were dried over anhydrous Na2SO4 and the sol-
vent was removed under reduced pressure to obtain the crude
product, which was purified by silica gel column chromatography
(60–120 mesh; EtOAc–hexane, 1:1) to afford 23. The spectral char-
acteristic data of 23 (1H NMR, 13C NMR and specific rotation) were
in perfect agreement with the literature values.14
ic layers were dried over anhydrous Na2SO4, the solvent was dis-
tilled off under reduced pressure, and the crude product was purified
by column chromatography (60–120 mesh; EtOAc–hexane, 1:24)
to give the corresponding alcohol 25.
Yield: 0.76 g (84%); liquid; Rf = 0.6 (silica gel; EtOAc–hexane,
2:8); [a]D25 –43.9 (c 1.1, CHCl3).
Yield: 1.15 g (80%); colorless oil; Rf = 0.2 (silica gel; EtOAc–
hexane, 1:1); [a]D25 –34.4 (c 1, CHCl3).
IR (neat): 3424, 2923, 1716, 1633, 1275, 1069, 770, 711 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (br s, 2 H, 2 × OH), 3.54 (dd,
J = 4.8, 11.7 Hz, 1 H, OCH), 3.54–3.64 (m, 1 H, CHOH), 3.67 (dd,
J = 2.9, 10.7 Hz, 1 H, CH2OH), 3.84 (t, J = 7.8 Hz, 1 H, CH2OH),
4.34 (d, J = 11.7 Hz, 1 H, CH2Ar), 4.64 (d, J = 11.7 Hz, 1 H,
CH2Ar), 5.34–5.42 (m, 2 H, 2 × =CH), 5.73–5.82 (m, 1 H, =CH),
7.23–7.38 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 63.1 (CH2OH), 70.7 (CH2Ar), 73.0
(CHOH), 82.2 (CH), 120.2 (=CH2), 127.8 (2 × CAr), 128.4 (CAr),
129.7 (2 × CAr), 134.8 (=CH), 137.7 (CAr).
MS (ESI): m/z = 231 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16O3Na: 231.0997;
IR (neat): 3452, 2977, 2870, 1453, 1259, 1068, 993, 930, 741, 698
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 (d, J = 6.2 Hz, 3 H, CH3),
2.60 (br s, 1 H, OH), 3.48 (t, J = 7.9 Hz, 1 H, OCH), 3.58–3.70 (m,
1 H, CHOH), 4.32 (d, J = 11.5 Hz, 1 H, CH2Ar), 4.62 (d,
J = 11.7 Hz, 1 H, CH2Ar), 5.27–5.4 (m, 2 H, 2 × =CH), 5.62–5.77
(m, 1 H, =CH), 7.21–7.36 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 18.3 (CH3), 69.5 (CH2Ar), 70.4
(CHOH), 86.1 (CH), 120.1 (=CH2), 127.7 (2 × CAr), 127.9 (CAr),
128.4 (2 × CAr), 135.4 (=CH), 138.0 (CAr).
MS (ESI): m/z = 215 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16O2Na: 215.1047;
found: 215.1047.
found: 231.1004.
(S)-[(2R,3R)-3-(Benzyloxy)pent-4-en-2-yl] 4-(tert-Butyldimeth-
ylsilyloxy)hept-6-enoate (26)
(R)-2-[(R)-1-(Benzyloxy)allyl]oxirane (24)9c
To a stirred solution of acid 20 (0.3 g, 1.16 mmol) in anhydrous
THF (4 mL), Et3N (0.3 mL, 2.32 mmol) was added at r.t. 2,4,6-
Trichlorobenzoyl chloride (0.19 mL, 1.27 mmol) was added and the
reaction mixture was further stirred at r.t. for 2 h then filtered and
the filtrate was evaporated. The residue was dissolved in toluene (4
mL), treated with DMAP (0.35 g, 2.9 mmol) and alcohol 25 (0.22
g, 1.16 mmol) in toluene (3 mL). The mixture was stirred at r.t. for
3 h and then diluted with EtOAc (10 mL), washed with sat. aq
NaHCO3 (2 × 5 mL), brine (20 mL), dried over Na2SO4, and con-
centrated under reduced pressure. The crude residue was purified by
silica gel column chromatography (60–120 mesh; EtOAc–hexane,
1:49) to afford ester 26.
To an ice-cold solution of diol 23 (1.5 g, 7.2 mmol), a catalytic
amount of dibutyl tin oxide (0.35 g, 1.4 mmol) and Et3N (1 mL, 8
mmol) in CH2Cl2 (15 mL) were added. A solution of TsCl (1.5 g, 8
mmol) in CH2Cl2 (10 mL) was added dropwise and the reaction was
stirred at r.t. for 4 h. After completion of reaction, the mixture was
diluted with H2O (5 mL) and extracted into CH2Cl2 (3 × 20 mL).
The organic layer was washed with brine (2 × 15 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure to give
the crude residue. This residue was dissolved in anhydrous MeOH
(10 mL), anhydrous K2CO3 (1.0 g, 7.6 mmol) was added at 0 °C and
the mixture was stirred at r.t. for 3 h. The reaction mixture was treat-
ed with sat. aq NH4Cl (5 mL), H2O (5 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was dried with
Na2SO4 followed by evaporation under reduced pressure and puri-
fication by silica gel column chromatography (60–120 mesh;
EtOAc–hexane, 5:95) to afford 24.
Yield: 0.4 g (80%); colorless liquid; Rf = 0.9 (silica gel; EtOAc–
hexane, 1:9); [a]D25 –13.4 (c 0.8, CHCl3).
IR (neat): 3075, 2930, 2857, 1735, 1456, 1364, 1253, 1077, 996,
835, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.87 [s,
9 H, C(CH3)3], 1.18 (d, J = 6.7 Hz, 3 H, CH3), 1.59–1.86 (m, 2 H,
CH2), 2.18 (t, J = 6 Hz, 2 H, CH2), 2.27–2.36 (m, 2 H, CH2), 3.69–
3.81 (m, 2 H, 2 × OCH), 4.37 (d, J = 12.8 Hz, 1 H, CH2Ar), 4.62 (d,
J = 12.1 Hz, 1 H, CH2Ar), 4.94–5.08 (m, 3 H, 2 × =CH, OCH),
5.25–5.35 (m, 2 H, 2 × =CH), 5.66–5.81 (m, 2 H, 2 × =CH), 7.24–
7.31 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = –4.6 (SiCH3), –4.4 (SiCH3), 15.9
(CH3), 18.0 [C(CH3)3], 25.8 [C(CH3)3], 30.2 (CH2), 31.5 (CH2),
41.7 (CH2), 70.3 (CH), 70.8 (CH2Ar), 71.3 (CH), 81.3 (CH), 117.0
(=CH2), 119.5 (=CH2), 127.5 (2 × CAr), 127.6 (CAr), 128.2 (2 × CAr),
134.3 (=CH), 134.6 (=CH), 138.2 (CAr), 173.2 (CO).
Yield: 75%; colorless oil; Rf = 0.7 (silica gel; EtOAc–hexane, 2:8);
[a]D25 +0.65 (c 1, CHCl3).
IR (neat): 3064, 2994, 2925, 2861, 1636, 1257, 1067, 934, 743, 699
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.52 (q, J = 3 Hz, 1 H, oxirane-H),
2.72 (t, J = 5.2 Hz, 1 H, oxirane-H), 2.99–3.05 (m, 1 H, oxirane-H),
3.53–3.59 (m, 1 H, OCH), 4.61 (q, J = 12 Hz, 2 H, CH2Ar), 5.24–
5.38 (m, 2 H, 2 × =CH), 5.79 (m, 1 H, =CH), 7.19–7.35 (m, 5 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 44.8 (oxirane-CH2), 53.9 (oxirane-
CH), 70.5 (CH2Ar), 81.0 (CH), 119.6 (=CH2), 127.6 (2 × CAr),
127.7 (CAr), 128.3 (2 × CAr), 134.3 (=CH), 138.0 (CAr).
MS (ESI): m/z = 433 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H40O4NaSi: 455.2593;
MS (ESI): m/z = 213 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14O2Na: 213.0891;
found: 455.2582.
found: 213.0892.
(S)-[(2R,3R)-3-(Benzyloxy)pent-4-en-2-yl] 4-Hydroxyhept-6-
enoate (28)
(2R,3R)-3-(Benzyloxy)pent-4-en-2-ol (25)4
To a stirred suspension of LiAlH4 (540 mg, 14.2 mmol) in THF (10
mL), was added dropwise a solution of 24 (0.9 g, 4.73 mmol) in
THF (10 mL) at 0 °C. The reaction mixture was stirred for 2 h at r.t.
and then cooled to 0 °C and the excess LiAlH4 was quenched by ad-
dition of EtOAc (5 mL). The reaction mixture was treated with 20%
NaOH (2 mL), the white precipitate formed was filtered off, and the
residue was washed with EtOAc (3 × 30 mL). The combined organ-
Compound 26 (0.2 g, 0.46 mmol) was dissolved in THF (2 mL) in
a plastic vial and HF·pyridine (1 mL) was added at 0 °C. The reac-
tion mixture was stirred at r.t. for 8 h then poured into cold sat. aq
NaHCO3 (5 mL) and extracted with EtOAc (2 × 10 mL). The organ-
ic layers were washed with sat. aq CuSO4 (2 × 5 mL), H2O (5 mL),
brine (2 × 10 mL), dried (Na2SO4) and concentrated under reduced
Synthesis 2011, No. 3, 451–458 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Stagonolide G from D-Mannitol
457
pressure. Silica gel column chromatography (60–120 mesh;
EtOAc–hexane, 2:8) gave pure alcohol 28.
Yield: 11 mg (68%); colorless liquid; Rf = 0.3 (silica gel; EtOAc–
hexane, 1:1); [a]D25 +6.4 (c 0.24, CHCl3).
Yield: 0.11 g (78%); colorless liquid; Rf = 0.4 (silica gel; EtOAc–
hexane, 2:8); [a]D25 –7.0 (c 0.16, CHCl3).
IR (neat): 3425, 2923, 2853, 1748, 1712, 1640, 1261 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14 (d, J = 6.0 Hz, 3 H, CH3),
1.88–2.08 (m, 1 H, CH), 2.26–2.44 (m, 2 H, CH2), 2.46–2.68 (m,
3 H, CH2, CH), 3.66–3.71 (m, 1 H, OCH), 4.07–4.14 (m, 1 H,
OCH), 4.51–4.59 (m, 1 H, OCH), 5.55–5.72 (m, 2 H, 2 × =CH).
13C NMR (100 MHz, CDCl3): d = 18.6 (CH3), 27.4 (CH2), 28.7
(CH2), 33.7 (CH2), 70.8 (CHOH), 72.2 (CH), 79.5 (CHOH), 127.8
(=CH), 132.4 (=CH), 177.0 (CO).
IR (neat): 3450, 3074, 2927, 2862, 1730, 1639, 1168, 1067, 926,
739, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.18 (d, J = 6.7 Hz, 3 H, CH3),
1.60–1.88 (m, 2 H, CH2), 2.07–2.34 (m, 2 H, CH2), 2.43 (t,
J = 6.7 Hz, 2 H, CH2), 3.57–3.68 (m, 1 H, OCH), 3.77 (t,
J = 6.7 Hz, 1 H, OCH), 4.36 (d, J = 12.1 Hz, 1 H, CH2Ar), 4.63 (d,
J = 12.1 Hz, 1 H, CH2Ar), 5.01 (t, J = 6.7 Hz, 1 H, =CH), 5.05–5.16
(m, 2 H, =CHOCH), 5.27–5.39 (m, 2 H, 2 × =CH), 5.66–5.85 (m,
2 H, 2 × =CH), 7.21–7.36 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 17.8 (CH3), 26.9 (CH2), 28.5
(CH2), 39.3 (CH2), 69.1 (CHOH), 70.1 (CH2Ar), 79.6 (CH), 84.1
(CH), 118.8 (=CH2), 120.2 (=CH2), 127.5 (2 × CAr), 127.6 (CAr),
128.2 (2 × CAr), 131.8 (=CH), 134.3 (=CH), 138.1 (CAr), 176.9
(CO).
MS (ESI): m/z = 201 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C10H16O4Na: 223.1335;
found: 223.1323.
Acknowledgment
The authors thank the Director, IICT and the Head Division Orga-
nic-II for encouragement of this Main Lab project work.
C.H.N.S.S.P., M.R. and S.N.K. thank CSIR, New Delhi for fel-
lowships.
MS (ESI): m/z = 319 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H26O4Na: 341.1728;
found: 341.1715.
References
(Z,5S,9R,10R)-9-(Benzyloxy)-3,4,5,6,9,10-hexahydro-5-hy-
droxy-10-methyloxecin-2-one (29)
(1) For reviews on synthetic, biosynthetic, and pharmacological
aspects of decanolides, see: (a) Dräger, G.; Kirschning, A.;
Thiericke, R.; Zerlin, M. Nat. Prod. Rep. 1996, 13, 365.
(b) Ferraz, H. M. C.; Bombonato, F. I.; Longo, L. S. Jr.
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A.; Motta, A. J. Nat. Prod. 2008, 71, 1897.
To a stirred solution of ester 28 (50 mg, 0.16 mmol) in freshly dis-
tilled, degassed, anhydrous CH2Cl2 (50 mL), Grubbs II catalyst (26
mg, 0.03 mmol) was added and the mixture was heated at reflux for
4 h under a nitrogen atmosphere. Most of the solvent was then dis-
tilled off and the concentrated solution was stirred at r.t. for 2 h un-
der air bubbling in order to decompose the catalyst. The reaction
mixture was evaporated to dryness to give a brown residue, which
was purified by silica gel column chromatography (60–120 mesh;
EtOAc–hexane, 1:3) to afford 29.
Yield: 29 mg (65%); colorless syrup; Rf = 0.4 (silica gel; EtOAc–
hexane, 1:1); [a]D25 –12.0 (c 0.2, CHCl3).
(3) (a) Srinivas, C. h.; Pavan Kumar, Ch. N. S. S.; China Raju,
B.; Jayathirtha Rao, V.; Naidu, V. G. M.; Ramakrishna, S.;
Diwan, P. V. Bioorg. Med. Chem. Lett. 2009, 19, 5915.
(b) Ravinder, M.; Sadhu, P. S.; Santhoshi, A.; Narender, P.;
Swamy, G. Y. S. K.; Ravi Kumar, K.; Jayathirtha Rao, V.
Synthesis 2010, 573. (c) Kumar, P. A.; Raman, D.; Murthy,
U. S. N.; Jayathirtha Rao, V. Bioorg. Chem. 2009, 37, 46.
(d) Kumar, P. A.; Raman, D.; Murthy, U. S. N.;
Jayathirtha Rao, V. Synth. Commun. 2010, 40, 686.
(e) Srinivas, C. h.; Pavan Kumar, Ch. N. S. S.; China Raju,
B.; Jayathirtha Rao, V. Helv. Chim. Acta 2011, in press;
DOI: 10.1002/hlca.201000291.
IR (neat): 3448, 2922, 2853, 1728, 1634, 1457, 1177, 1067, 698
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.05 (d, J = 6.2 Hz, 3 H, CH3),
1.87–2.04 (m, 2 H, CH2), 2.18–2.55 (m, 4 H, 2 × CH2), 3.61–3.73
(m, 1 H, OCH), 3.82 (t, J = 7.9, 9 Hz, 1 H, OCH), 4.29 (d,
J = 11.7 Hz, 1 H, CH2Ar), 4.39–4.52 (m, 1 H, OCH), 4.57 (d,
J = 11.5 Hz, 1 H, CH2Ar), 5.42 (td, J = 11.3, 9.8 Hz, 1 H, =CH),
5.74 (qt, J = 11.3, 7.5 Hz, 1 H, =CH), 7.21–7.33 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 18.3 (CH3), 28.9 (CH2), 32.1
(CH2), 34.3 (CH2), 69.8 (CHOH), 70.6 (CH2Ar), 79.7 (CH), 79.9
(CH), 123.6 (=CH), 128.0 (=CH), 128.7 (2 × CAr), 130.0 (CAr),
130.6 (2 × CAr), 135.4 (CAr), 176.0 (CO).
(4) Srihari, P.; Kumaraswamy, B.; Bhunia, D. C.; Yadav, J. S.
Tetrahedron Lett. 2010, 51, 2903.
MS (ESI): m/z = 291 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H22O4Na: 313.1415;
(5) (a) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips,
J. L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C.
S. J. Org. Chem. 1991, 56, 4056. (b) Chattopadhyay, A.;
Mamdapur, V. R. J. Org. Chem. 1995, 60, 585.
found: 313.1406.
(Z,5S,9R,10R)-3,4,5,6,9,10-Hexahydro-5,9-dihydroxy-10-meth-
yloxecin-2-one (6)2b,4
(c) Sugiyama, T.; Suguwara, H.; Watanabe, M.; Yamashita,
K. Agric. Biol. Chem. 1984, 48, 1841.
To a solution of THF (2 mL) and liq. NH3 (5 mL), Na (8 mg, 0.37
mmol) was added and the reaction mixture was stirred for 10 min at
–78 °C. Compound 29 (25 mg, 0.09 mmol) in THF (1 mL) was add-
ed and the mixture was stirred further for 10 min at the same tem-
perature. The reaction was quenched with solid NH4Cl, filtered,
diluted with EtOAc (10 mL), dried (Na2SO4), and concentrated un-
der reduced pressure. The crude residue was purified by silica gel
column chromatography (60–120 mesh; EtOAc–hexane, 1:2) to af-
ford 6.
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