Effect of the allylic substituents on ring closing metathesis: The total synthesis of stagonolide B and 4-epi-stagonolide B

Article abstract of DOI:10.1039/b916198h

The total syntheses of stagonolide B and its 4-epimer were carried out to probe into how the relative stereochemistry of allylic hydroxy groups and their protecting groups influence the efficiency of the ring closing metathesis.

Full text of DOI:10.1039/b916198h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Effect of the allylic substituents on ring closing metathesis: the total synthesis
of stagonolide B and 4-epi-stagonolide B†
Awadut G. Giri, Mohabul A. Mondal, Vedavati G. Puranik and Chepuri V. Ramana*
Received 6th August 2009, Accepted 29th September 2009
First published as an Advance Article on the web 29th October 2009
DOI: 10.1039/b916198h
The total syntheses of stagonolide B and its 4-epimer were carried out to probe into how the relative
stereochemistry of allylic hydroxy groups and their protecting groups influence the efficiency of the ring
closing metathesis.
nonenolide constructions with the 2-ene-1,4-diol unit revealed that
they all dealt with RCM of the substrates leading to 1,4-cis-diol-
Introduction
configured nonenolides,6 and reports dealing with the construction
of nonenolides with a 1,4-trans-diol configuration are scarce.7
Intrigued by this, we have selected the stagonolide B,9 which
presents such a 2E-ene-1,4-trans-diol unit as a representative
natural product in order to explore its total synthesis, employing
RCM as the key reaction.8–10
Since the first construction of a 10-membered lactone using ring
closing metathesis (RCM) by Fu¨rstner and Thomas in 1997,1
the synthesis of numerous naturally occurring ten-membered ring
lactones, generally referred as nonenolides, have been documented
by employing the RCM construct.2,3 Though RCM has become a
multipurpose reaction in nonenolide synthesis, the outcome of the
reaction is sensitive to multiple factors, such as the nature of the
catalyst,4 and the steric crowding around the newly forming ring-
olefin.5,6a Sometimes, even the success of RCM is substrate-specific.
In dealing with the synthesis of multiplolide A,5 it was noticed
that amongst the four similar substrates employed, only one of
the substrates provided the desired 10-membered macrolactone.
For example, RCM was found to be facile in constructing the
macrolide D (a 1,4-cis-diol), whereas in the construction of the
macrolide C, with a 1,4-trans-diol configuration, RCM led to
oligomerization. A close examination of the available RCM-based
In 2007, Berestetskiy and co-workers described the isolation,
and chemical and biological characterization of a new nonenolide
produced by Stagonospora cirsii (a pathogen of Cirsium arvense)
in liquid cultures, named stagonolide.8 The relative and the
absolute stereochemical structure of stagonolide was established
by converting it to the known herbarumin I employing a NaBH4
reduction of the keto group. Later, in 2008, Evidente et al. reported
the isolation of five new nonenolides from the same fungus, grown
in solid culture.9 Considering their origin and structural similarity,
these five new nonenolides were named as stagonolides B–F. The
similarity in the spectral data of 1–6 with the previously reported
natural products herbarumins was taken into account in assigning
the connectivity of the free hydroxyl groups in stagonolides. Their
relative orientations have been proposed as given in Fig. 1. Herein,
we describe the first total synthesis of stagonolide B and its
4-epimer by employing RCM for the construction of the central
nonenolide core with the required E-stereochemistry of the ring
olefin.
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008,
India. E-mail: vr.chepuri@ncl.res.in; Fax: +91 20 25902629; Tel: +91 20
25902577
† Electronic supplementary information (ESI) available: X-Ray crystal
structure data and co-ordinates of epi-2, 1H and 13C NMR spectra of
2 and epi-2, and the Moscher model for the determination of absolute
stereochemistry of alcohol (R)-10. CCDC 743822. For crystallographic
data in CIF or other electronic format, see DOI: 10.1039/b916198h
Fig. 1 The end results of RCM-mediated construction of selected nonenolides with a 2-ene-1,4-diol unit, and structures of recently isolated
stagonolides A–F.
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by further oxidation of intermediate aldehyde employing sodium
hypochlorite under buffered conditions,15 completed the synthesis
of the acid fragment (R)-8. The acetate (S)-14 was subjected to
deacetylation and the resulting (S)-10 was used for the synthesis
of (S)-8 employing the same sequence of reactions as used for its
enantiomer synthesis.
The alcohol fragment 9 was synthesized from D-ribose. The
known ribose 2,3-acetonide 11 was prepared according to the
reported procedure and subjected to one carbon Wittig homolo-
gation to afford the 1,2-diol 17.16 Selective 1◦-OH tosylation of 17
followed by base treatment furnished the epoxide 19.17 Opening
of the oxirane by using EtMgBr needed some experimentation,
as the formation of the corresponding bromohydrin was the
competing reaction. Under optimized conditions, we could isolate
the requisite coupling partner 9 in 71% yield, with identical
spectral and analytical data to that reported earlier.4
Results and discussion
The key retrosynthetic disconnections are given in Fig. 2. After
the application of the RCM transformation, the enantiomeric
acids (R)-8 and (S)-8, and the alcohol 9 were identified as the
key coupling partners for the synthesis of stagonolide B (2) and
its 4-epimer epi-2. Easily available D-ribose has been selected as a
starting point for the chiral pool synthesis of the known alcohol
fragment 9.4,11 The synthesis of the enantiomeric acids 8 was
planned through the enzymatic resolution of the TBS-protected
hex-5-ene-1,4-diol 10.12 A PMB protection on the allylic –OH of
the acid coupling partner was selected as a safe handle to change
the steric nature of the adjacent functional groups that have been
shown to influence the outcome of the RCM.5,6a,7
Our next concern was the execution of the key macrolide
construction. The RCM precursor 7 was obtained by the coupling
of acid (R)-8 and alcohol 9 using the Yamaguchi reagent.18 Various
catalysts prescribed for the metathesis have been explored with
this substrate 7, the RCM of which turned out to be a difficult
proposition. Anticipating this problem, we have opted for the PMB
deprotection, which indeed was selected a priori as a safe handle.5
The PMB deprotection was carried out with DDQ to afford the
diene ester 20. The attempted RCM of 20 was found to mainly
yield the oligomeric products with both the 1st and 2nd generation
catalysts of Grubbs’ and Hoveyda–Grubbs’ in solvents such as
dichloromethane, benzene and toluene, either at rt or at reflux
temperatures. Finally, when we switched to dichloroethane as a
solvent,3d,19 and employed 2nd gen. Grubbs’/Hoyeda–Grubbs’
catalysts, we noticed the molecular ion peaks corresponding to
the product in the LCMS.
After examining the various reaction parameters, the RCM of
20 could be conducted successfully using 25 mol% of 2nd gen.
Grubbs’ catalyst in dichloroethane at reflux temperature. As the
separation of the resulting lactone was found to be tedious, the
crude RCM reaction mixture was advanced for the acetonide de-
protection employing TFA at 0 ◦C for 1 h to afford the stagonolide
B (2) in moderate yields. The analytical and spectral data of 2
were in agreement with the data reported for the natural product.
The sign and magnitude of the specific rotation of synthetic
stagonolide B confirmed the assigned absolute configuration of
natural stagonolide B.9
At the outset, to check the validity of our assumption, the diene
epi-7 was prepared by coupling the acid (S)-8 and alcohol 9. As
expected, the RCM of the fully protected diene ester epi-7 was
facile with the 2nd gen. Grubbs’ catalyst in toluene at 80 ◦C and
gave 21 in 69% yield. The global deprotection of 21 by employing
TFA gave the 4-epi-stagonolide B (epi-2) as a white solid and its
structure was confirmed from the spectral, analytical and single
crystal X-ray diffraction data (Scheme 2 and Fig. 3).
The difference in the outcome of the RCM reaction with
respect to the relative stereochemistry of the allylic positions of
dienes 7 and epi-7 is particularly striking. This could be due
to the conformational constraints during the formation of the
ruthenacyclobutane.4,7 Gennari and co-workers earlier reported
a systematic investigation on the role of protecting groups
and the stereochemistry of the allylic hydroxyl groups on the
10-membered carbocycle construction.7,22 The RCM was
Fig. 2 Retrosynthetic analysis for stagonolide B.
The synthesis begin with the preparation of the acids (R)- and
(S)-8 (Scheme 1). Readily available 4-pentene-1-ol was converted
to the epoxide 13. The one carbon extension of the epoxide13
was carried out using trimethyl sulfonium iodide and n-BuLi
in THF to afford the key allyl alcohol 10. Alcohol 10, upon
treatment with Amano PS, afforded alcohol (R)-10 [ee = 82%,
corresponding acetate (R)-14] and acetate (S)-14 (ee = 97%).12
The enantiomeric excess was determined by GC analysis of the
acetates and the absolute configuration of the alcohol (R)-10
was established by using the Mosher ester method.14 Protection
of the hydroxyl group of (R)-10 as its PMB ether, followed
by silyl deprotection using TBAF, gave (R)-16. Oxidation of
alcohol 16 to the aldehyde under Swern conditions, followed
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Scheme 1 Reagents and conditions: (a) Me3S+I-, n-BuLi, THF, -78 ◦C→rt, 7 h; (b) Amano PS, benzene : petroleum ether (1 : 3), vinyl acetate, 40 ◦C,
96 h; (c) PMBCl, DMF, 60% NaH, 0→rt, 4 h; (d) TBAF, THF, rt, 4 h; (e) i. (COCl)2, DMSO, Et3N, DCM, -78 ◦C, 1 h; ii. NaClO2, NaH2PO4, DMSO,
H2O, 10 h; (f) K2CO3, MeOH, rt, 1 h.
Scheme 2 Reagents and conditions: (a) p-TsCl, TEA, DCM, 0 ◦C, 4 h; (b) MeOH, K2CO3, rt, 10 h; (c) EtMgBr, CuCN, Et2O, 0 ◦C, 1 h;
(d) 2,4,6-trichlorobenzoyl chloride, DMAP, ethyldiisopropylamine, 16 h; (e) DDQ, DCM–H2O, 3 h; (f) 25 mol% 2nd gen. Grubbs’ catalyst,
1,2-dichloroethane, reflux 24 h; (g) TFA, 0 ◦C, 1 h; (h) 10 mol% 2nd gen. Grubbs’ catalyst, toluene, 80 ◦C, 6 h; (i) 10 mol% 2nd gen. Grubbs’
catalyst, DCM, reflux, 6 h.
protecting group-specific. With PMP protection on both the allylic
hydroxyl groups, 10-membered carbocycles with 2E-ene-1,4-cis-
or trans-diol were obtained under forced RCM conditions, the
former being obtained in good yields and the latter in poor yields.
With both the MOM and methyl ether derivatives, the RCM led
mainly to oligomerization.
trans configuration, might be because of the steric crowding,
which persists on both faces during the formation of the
ruthenacyclobutane.7b,20,21 For the formation of a macrocycle with
a 1,4-cis configuration (with epi-7), such a steric crowding is absent
as both these allylic groups lie on the same face. A simple rotation
around the C–C bond in the case of the former dienes also leads to
the ruthenacyclobutane having both the allylic groups on the same
face. This may provide a possible explanation for the competing
The difficulties noticed with dienes such as 7 leading to a
10-membered macrocycle bearing allylic substituents with 1,4-
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and diethyl ether from Na and benzophenone; MeOH, (CH2)2Cl2
and CH2Cl2 from CaH2. Commercial reagents were used without
purification. Column chromatography was carried out by using
Spectrochem silica gel (60–120, 230–400 mesh). Optical rotations
were determined on a Jasco DIP-370 digital polarimeter. Specific
1
optical rotations [a]D are given in 10-1 deg cm2 g-1. H and 13C
NMR spectroscopy measurements were carried out on Bruker
AC 200 MHz, Bruker DRX 400 MHz or Bruker DRX 500 MHz
1
spectrometers, and TMS was used as the internal standard. H
and 13C NMR chemical shifts are reported in ppm downfield from
tetramethylsilane and coupling constants (J) are reported in hertz
(Hz). The following abbreviations are used to designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad. Mass spectroscopy (ESI, API-QStar
Pulsar) was carried out on a Finnigan MAT-1020 spectrometer.
GC analyses were carried out on Agilent Technologies 7890 Model
machine using HP-Chiral-20B (30 m ¥ 0.32 mm ¥ 0.25 m) column.
Elemental analysis data were obtained on a Thermo Finnigan
Flash EA 1112 Series CHNS Analyser.
Fig. 3 The molecular structure of 4-epi-stagonolide B. Displacement
ellipsoids are drawn at the 50% probability level. H atoms are represented
by circles of an arbitrary radius.
di-/oligomerization reaction when the ring closure is sterically
demanding.22
The feasibility of RCM with 20 (where one of the allylic
hydroxy groups is free) could, to some extent, be explained by
anticipating a co-operative O–H ◊ ◊ ◊ Cl–Ru hydrogen bonding.23c
The acceleration of RCM reaction rates with free allylic hydroxyl
groups is well documented.20 It has been shown recently that
such acceleration by an allylic –OH group was also regio-23a,b
and stereoselective.23c In this regard, diene epi-20 bearing a free
allylic –OH was prepared and subjected to ring closing metathesis
using 2nd generation Grubbs’ catalyst. The ring closure of epi-
20 was facile and even more productive when compared with
the corresponding PMB-protected diene epi-7. The RCM of
epi-20 could be carried out smoothly in dichloromethane at
reflux and E/Z noneolides 22 were obtained in an 11 : 1 ratio.
Carrying out the reaction under conditions similar to those for
epi-7 (toluene, 80 ◦C) resulted in an increase of the Z-isomer
(7 : 1 ratio). These results are indicative of the influence of the
relative stereochemistry of the hydroxyl group on the RCM rate
acceleration by the ruthenium catalyst. Though these limited
examples provide clues as to where the RCM could be a difficult
proposition, a more comprehensive examination is needed with
a broad range of substrates varying the stereochemistry of other
centers and also without any conformational rigidity such as an
acetonide protecting group. Work in this direction is progressing
in our lab.
4-O-(tert-Butyldimethylsilyl)-hex-5-ene-1,4-diol (10)
A solution of trimethyl sulfonium iodide (7.5 g, 36.7 mmol) in
THF (100 mL) was cooled to -78 ◦C and treated with n-BuLi
(13.8 ml, 32.4 mmol) and stirred for 20 min. To this, a solution
of 13 (2.0 g, 9.2 mmol) in THF (10 mL) was added slowly and
stirred at -78 ◦C for 1 h and at rt for 6 h. The reaction mixture was
partitioned between water and EtOAc. The aqueous phase was
extracted with EtOAc. The combined organic phase was dried
(Na2SO4), filtered and concentrated under reduced pressure. The
purification of residue by silica gel column chromatography (5%
ethyl acetate in petroleum ether) gave 10 (1.67 g, 79%) as a colorless
oil. IR (CHCl3): 3370, 2930, 2858, 1472, 1256, 835 cm-1. 1H NMR
(200 MHz, CDCl3): d 0.04 (s, 6H), 0.88 (s, 9H), 1.57–1.67 (m,
4H), 2.77 (br. s, 1H), 3.63 (br. t, J = 5.8 Hz, 2H), 4.11 (dd, J =
5.8, 11.0 Hz, 1H), 5.06 (ddd, J = 1.2, 1.7, 10.4 Hz, 1H), 5.21 (dt,
J = 1.6, 17.2 Hz, 1H), 5.85 (ddd, J = 5.9, 10.4, 17.2 Hz, 1H). 13
C
NMR (50 MHz, CDCl3): d -5.4 (q), 18.3 (s), 25.9 (q), 28.7 (t), 34.3
(t), 63.3 (t), 72.6 (d), 114.2 (t), 141.2 (d) ppm. ESI-MS m/z: 231.4
(42.8%, [M + H]+), 253.4 (100%, [M + Na]+), 269.4 (28.6%, [M +
K]+). Anal. Calcd for C12H26O2Si: C, 62.55; H, 11.37; Found: C,
62.41; H, 11.66%.
Conclusions
Amano PS-mediated resolution of (RS)-10
The first total synthesis of stagonolide B (2) confirming its absolute
stereochemistry has been documented. A combination of the
chiral pool approach and enzymatic resolution has been adopted
to synthesize the key coupling partners. The 4-epi-stagonolide B
has also been synthesized to check the influence of the relative
stereochemistry of allylic hydroxy groups and their protecting
groups on the efficiency of the RCM and on the rate acceleration
by the catalyst.
A suspension of (RS)-10 (2.2 g, 9.5 mmol), Amano PS (600 mg)
and vinyl acetate (4.4 mL, 47.8 mmol) in benzene–petroleum ether
(50 mL, 1 : 2) was heated at 40 ◦C for 96 h. The contents were
filtered and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(2→5% ethyl acetate in petroleum ether) to afford alcohol (R)-10
(0.9 g, 41%) and acetate (S)-14 (1.1 g, 42%) as colorless oils.
(4R)-4-O-(tert-Butyldimethylsilyl)-hex-5-ene-1,4-diol [(R)-10]
Experimental
[a]2D5 = -1.9 (c 1.0, CHCl3). IR (CHCl3): 3370, 2930, 2858, 1472,
1256, 835 cm-1. 1H NMR (200 MHz, CDCl3): d 0.04 (s, 6H), 0.88
(s, 9H), 1.57–1.67 (m, 4H), 2.77 (br. s, 1H), 3.63 (t, J = 5.8 Hz,
2H), 4.11 (br. q, J = 5.7 Hz, 1H), 5.06 (ddd, J = 1.3, 1.6, 10.3 Hz,
1H), 5.21 (dt, J = 1.5, 17.2 Hz, 1H), 5.85 (ddd, J = 5.8, 10.3,
General methods
Air and/or moisture sensitive reactions were carried out in
anhydrous solvents under an atmosphere of argon in oven-dried
glassware. All anhydrous solvents were distilled prior to use: THF
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17.3 Hz, 1H). 13C NMR (50 MHz, CDCl3) d: -5.4 (q), 18.3 (s),
25.9 (q), 28.7 (t), 34.3 (t), 63.3 (t), 72.6 (d), 114.2 (t), 141.2 (d) ppm.
ESI-MS m/z: 231.4 (42.8%, [M + H]+), 253.4 (100%, [M + Na]+),
269.4 (28.6%, [M + K]+). Anal. Calcd for C12H26O2Si: C, 62.55; H,
11.37; Found: C, 62.67; H, 11.53%.
(t), 31.8 (t), 55.1 (q), 63.0 (t), 69.6 (t), 80.0 (d), 113.7 (d), 116.9 (t),
129.2 (d), 130.8 (s), 139.2 (d), 159.0 (s) ppm. ESI-MS m/z: 351.0
(100%, [M + H]+). Anal. Calcd for C20H34O3Si: C, 68.52; H, 9.78;
Found: C, 68.61; H, 9.88%.
(S)-15
(4S)-1-O-Acetyl-4-O-(tert-butyldimethylsilyl)-hex-5-ene-1,4-diol
[(S)-14]
[a]2D5 = -17.5 (c 1, CHCl3); Anal. Calcd for C20H34O3Si: C, 68.52;
H, 9.78; Found: C, 68.19; H, 9.92%.
Rt = 25.47 (Flow rate: 1.1073 ml min-1, 60 ◦C/10 min,
5 ◦C◦min-1 → 80 ◦C then 10 ◦C min-1 → 140 ◦C and 10 ◦C min-1
→
(4R)-1-O-(4-Methoxybenzyl)-hex-5-ene-1,4-diol [(R)-16]
220 C/5 min). [a]D25 = -6.0 (c 1.0, CHCl3); Lit.12 [a]2D4 = -6.1 (c
1.28, CHCl3). IR (CHCl3): 2955, 2858, 1742, 1560, 1473, 1248,
To a cooled solution of 15 (3.0 g, 8.5 mmol) in dry THF (40 mL)
was added tetrabutyl ammonium fluoride (2.68 g, 10.2 mmol)
and stirred at rt for 4 h. The reaction mixture was partitioned
in sat. ammonium chloride and ethyl acetate and the aqueous
layer was extracted with ethyl acetate. The combined extracts were
dried (Na2SO4) and concentrated under reduced pressure. The
purification of residue by silica gel column chromatography (25%
ethyl acetate in petroleum ether) gave (R)-16 (1.80 g, 89% yield)
as a colorless oil. [a]2D5 = +19.4 (c 0.9, CHCl3). IR (CHCl3): 3020,
2928, 2855, 1612, 1514, 1215, 1035, 758 cm-1. 1H NMR (200 MHz,
CDCl3): d 1.59–1.67 (m, 4H), 1.96 (br. s, 1H), 3.57–3.63 (m, 2H),
3.71–3.79 (m, 4H), 4.27 (d, J = 11.4 Hz, 1H), 4.53 (d, J = 11.4 Hz,
1H), 5.21 (br. ddd, J = 0.9, 1.8, 16.2 Hz, 1H), 5.23 (br. ddd, J =
0.7, 1.8, 11.3 Hz, 1H), 5.76–5.83 (m, 1H), 6.86 (br. d, J = 8.6 Hz,
2H), 7.25 (br. d, J = 8.6 Hz, 2H). 13C NMR (50 MHz, CDCl3):
d 28.8 (t), 32.3 (t), 55.2 (q), 62.8 (t), 69.8 (t), 80.1 (d), 113.8 (d),
117.2 (t), 129.4 (d), 130.4 (s), 138.7 (d), 159.1 (s) ppm. ESI-MS
m/z: 237.4 (8.3%, [M + H]+), 259.4 (100%, [M + Na]+), 275.4
(20.8%, [M + K]+). Anal. Calcd for C14H20O3: C, 71.16; H, 8.53;
Found: C, 70.9; H, 8.69%.
1
1100, 835 cm-1. H NMR (200 MHz, CDCl3): d 0.03 (s, 6H),
0.87 (s, 9H), 1.44–1.72 (m, 4H), 2.05 (s, 3H), 3.60 (t, J = 6.2 Hz,
2H), 5.12–5.28 (m, 1H), 5.79 (ddd, J = 6.2, 10.4, 17.4 Hz, 1H).
13C NMR (50 MHz, CDCl3): d -5.5 (q), 18.3 (s), 21.2 (q), 25.9
(q), 28.3 (t), 30.5 (t), 62.2 (t), 74.5 (d), 116.6 (t), 136.5 (d), 170.3
(s) ppm. ESI-MS m/z: 295.3 (100%, [M + Na]+). Anal. Calcd for
C14H28O3Si: C, 61.72; H, 10.36; Found: C, 61.64; H, 10.19%.
(R)-14
Rt = 25.40 (Flow rate: 1.1073 ml min-1, 60 ◦C/10 min,
5 ◦C◦min-1 → 80 ◦C then 10 ◦C min-1 → 140 ◦C and 10 ◦C min-1
→
220 C/5 min). [a]2D5 = +5.2 (c 1.0, CHCl3). Anal. Calcd for
C14H28O3Si: C, 61.72; H, 10.36; Found: C, 61.84; H, 10.19%.
(4S)-4-O-(tert-Butyldimethylsily)-hex-5-ene-1,4-diol [(S)-10]
To a solution of (S)-14 (2 g, 7.3 mmol) in methanol (20 mL) was
added K2CO3 (2 g, 14.7 mmol) and reaction mixture stirred at
rt for 1 h and filtered and the filtrate was concentrated under
reduced presser. The residue was purified by silica gel column
chromatography (2→5% ethyl acetate in petroleum ether) to afford
alcohol (S)-10 (1.5 g, 91%) as colorless oil. [a]2D5 = +1.8 (c 1,
CHCl3); Anal. Calcd for C12H26O2Si: C, 62.55; H, 11.37; Found:
C, 62.70; H, 11.41%.
(S)-16
[a]2D5 = -23.6 (c 1, CHCl3); Anal. Calcd for C14H20O3: C, 71.16; H,
8.53; Found: C, 71.02; H, 8.73%.
(4R)-1-O-(4-Methoxybenzyl)-4-O-(tert-butyldimethylsilyl)-hex-5-
ene-1,4-diol [(R)-15]
(4R)-4-(4-Methoxybenzyloxy)hex-5-enoic acid [(R)-8]
At -78 ◦C, a solution of DMSO (1.8 mL, 25.4 mmol) in CH2Cl2
(30 mL) was treated with oxalyl chloride (1.9 mL, 21.1 mmol) and
stirred for 20 min. To this alcohol, (R)-16 (2.0 g, 8.4 mmol) was
added slowly and stirring was continued at -78 ◦C for another 1 h.
To this, triethylamine (6 mL, 43 mmol) was added and the contents
were allowed to warm to rt. The reaction mixture was poured into
aqueous NH4Cl (10 mL) and extracted with EtOAc. The combined
organic layer was washed with water (20 mL), dried (Na2SO4)
and concentrated under reduced pressure and the resulting crude
aldehyde was used directly for next step.
To a cooled solution of the above aldehyde (1.8 g) in DMSO
(10 mL) and aq. NaH2PO4·2H2O (0.8 g in 5 mL water), a solution
of sodium chlorite (1.8 g, 19.8 mmol) in water (10 mL) was
introduced slowly and the resulting mixture was stirred at rt for
10 h. The reaction mixture was diluted with water and extracted
with ethyl acetate. The organic extract was dried (Na2SO4) and
concentrated. The crude product was purified by silica gel column
chromatography (25→30% ethyl acetate in petroleum ether) to
obtain acid (R)-8 (1.28 g, 61%) as a colorless oil.
To a cooled solution of (R)-10 (3.4 g, 14.7 mmol) in anhydrous
DMF (35 mL), NaH (60% dispersion in mineral oil, 620 mg,
15.5 mmol) was added slowly and stirred for 5 min. Then PMB-
Cl (2.2 mL, 16.2 mmol) was added and stirring continued at
room temperature for 4 h. The reaction mixture was partitioned
between water and EtOAc, and the aqueous layer was extracted
with EtOAc. The combined organic layer was dried (Na2SO4) and
concentrated under reduced pressure. Purification of the residue
by silica gel column chromatography (1→3% ethyl acetate in
petroleum ether) afforded (R)-15 (3.82 g, 75%) as a colorless oil.
[a]2D5 = +13.4 (c 0.7, CHCl3). IR (CHCl3): 2954, 2857, 1613, 1514,
1250, 1097, 835 cm-1. 1H NMR (200 MHz, CDCl3): d 0.03 (s, 6H),
0.89 (s, 9H), 1.50–1.68 (m, 4H), 3.59 (br. t, J = 5.8 Hz, 2H), 3.67–
3.77 (m, 1H), 3.79 (s, 3H), 4.28 (d, J = 11.5 Hz, 1H), 4.53 (d, J =
11.5 Hz, 1H), 5.19 (br. ddd, J = 0.8, 1.9, 16.2 Hz, 1H), 5.22 (br.
ddd, J = 0.7, 1.9, 11.2 Hz, 1H), 5.65 (br. ddd, J = 7.6, 11.2, 16.2 Hz
1H), 6.86 (br. d, J = 8.6 Hz, 2H), 7.25 (br. d, J = 8.6 Hz, 2H).
13C NMR (50 MHz, CDCl3) d: -5.35 (q), 18.3 (s), 25.9 (q), 28.6
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(R)-8
17.1 Hz, 1H). 13C NMR (50 MHz, CDCl3): d 25.1 (q), 27.6 (q),
45.7 (d), 49.7 (d), 78.6 (d), 78.9 (d), 109. (s), 118.8 (t), 132.4 (d) ppm.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29 Found: C, 63.35; H,
8.18%.
[a]2D5 = +23.2 (c 1.0, CHCl3). IR (CHCl3): 3076, 1710, 1612, 1514,
1422, 1249, 1035, 910, 734 cm-1. 1H NMR (200 MHz, CDCl3): d
1.81–1.94 (m, 2H), 2.43 (br. dd, J = 7.1 Hz, 2H), 3.73–3.83 (m,
4H), 4.27 (d, J = 11.4 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 5.26 (br.
ddd, J = 0.7, 1.8, 10.9 Hz, 1H), 5.25 (br. ddd, J = 0.9, 1.8, 16.6 Hz,
1H), 5.65–5.82 (m, 1H), 6.6 (br. d, J = 8.7 Hz, 2H), 7.25 (br. d,
J = 8.7 Hz, 2H). 13C NMR (50 MHz, CDCl3): d 30.1 (t), 30.1
(t), 55.2 (q), 69.8 (t), 78.8 (d), 113.7 (d), 117.8 (t), 129.4 (d), 130.3
(s), 138.1 (d), 159.1 (s), 179.2 (s) ppm. ESI-MS m/z: 273.2 (100%,
[M + Na]+), 289.2 (12.4%, [M + K]+). Anal. Calcd for C14H18O4:
C, 67.18; H, 7.25; Found: C, 67.55; H, 7.32
(3S,4R,5S)-3,4-O-Isopropylidene-oct-1-ene-3,4,5-triol (9)
At 0 ◦C, a suspension of CuCN (1.64 g, 18.2 mmol) in dry ether
(10 mL) was treated with a solution of EtMgBr [prepared from
Mg (1.85 g, 76 mmol) and ethyl bromide (3.42 mL, 45.6 mmol)]
in ether (30 mL) added slowly, and the contents were stirred at
0
◦C for 20 min. To this, a solution of the epoxide 19 (2.59 g,
15.2 mmol) in ether (10 mL) was introduced and the mixture was
stirred for another 1 h at 0 ◦C. The reaction mixture was quenched
with cold water and extracted with ethyl acetate. The combined
organic extract was dried (Na2SO4), concentrated and the resulting
crude material was purified by column chromatography to afford
alcohol 9 (2.1 g, 71%) as a colorless oil. [a]2D5 = +9.9 (c 1.3, CHCl3).
IR (CHCl3): 3437, 2987, 2959, 2936, 2874, 1458, 1428, 1381, 1253,
(S)-8
[a]2D5 = -27.4 (c 1.0, CHCl3). Anal. Calcd for C14H18O4: C, 67.18;
H, 7.25; Found: C, 67.83; H, 7.12%
1,2-Dideoxy-2,3-O-isopropylidene-5-O-(p-toluenesulfonyl)-D-ribo-
hex-1-enitol (18)
1
1217, 1168, 1099, 1067, 1033, 874 cm-1. H NMR (200 MHz,
CDCl3): d 0.92 (t, J = 6.9 Hz, 3H), 1.31–1.72 (m, 4H), 1.35 (s,
3H), 1.46 (s, 3H), 3.66 (br. t, J = 8.5 Hz, 1H), 3.96 (dd, J =
6.5, 8.2 Hz, 1H), 4.63 (br. t, J = 6.9 Hz, 1H), 5.30 (br. d, J =
10.3 Hz, 1H), 5.41 (br. d, J = 17.2 Hz, 1H), 6.03 (ddd, J = 7.7,
10.2, 17.2 Hz, 1H). 13C NMR (50 MHz, CDCl3): d 14.0 (q), 18.3
(t), 25.3 (q), 27.8 (q), 35.8 (t), 69.7 (d), 78.9 (d), 80.7 (d), 108.6 (s),
118.5 (t), 134.7 (d) ppm. Anal. Calcd for C11H20O3: C, 65.97; H,
10.07 Found: C, 65.83; H, 9.84%.
A solution of diol 17 (10.0 g, 53.2 mmol) in dry CH2Cl2 (150 mL)
was cooled to 0 ◦C and treated with TsCl (10.25 g, 53.7 mmol)
followed by TEA (22.3 mL, 161 mmol) and stirred at rt for
4 h. Then reaction mixture was partitioned between water and
CH2Cl2, and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with water, dried (Na2SO4)
and concentrated under reduced pressure. The crude product
was purified by column chromatography (25% ethyl acetate in
petroleum ether) to afford 18 (15.46 g, 85%) as a pale yellow oil.
[a]2D5 = +25.5 (c 1.1, CHCl3). 1H NMR (200 MHz, CDCl3): d 1.28
(s, 3H), 1.37 (s, 3H), 2.38 (br. s, 1H), 2.43 (s, 3H), 3.76–3.87 (m,
1H), 3.97 (dd, J = 6.1, 8.8 Hz, 1H), 4.05 (dd, J = 6.6, 10.3 Hz,
1H), 4.28 (dd, J = 2.2, 10.3 Hz, 1H), 4.66 (br. tt, J = 1.2, 6.3 Hz,
1H), 5.25 (dt, J = 1.2, 10.4 Hz, 1H), 5.40 (dt, J = 1.4, 17.2 Hz,
1H), 5.91 (ddd, J = 6.6, 10.4, 17.2 Hz, 1H), 7.33 (br. d, J = 8.3 Hz,
2H), 7.79 (br. d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 21.5 (q), 25.1 (q), 27.4 (q), 68.0 (d), 72.2 (t), 76.9 (d), 78.1 (d),
109.0 (s), 118.1 (t), 127.9 (d), 129.8 (d), 132.5 (s), 133.0 (d), 144.9
(s) ppm. Anal. Calcd for C16H22O6S: C, 56.12; H, 6.48; Found: C,
55.89; H, 6.51%.
Diene 7
To a solution of acid (R)-8 (500 mg, 2.0 mmol) in dry THF
(10 mL) were added 2,4,6-trichlorobenzoyl chloride (0.37 mL,
2.4 mmol) and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol)
and the contents were stirred for 2 h at ambient temperature. After
completion of mixed anhydride formation as indicated by TLC,
DMAP (500 mg, 4 mmol) and a solution of alcohol 9 (400 mg,
2.0 mmol) in THF (2 mL) were added and the reaction mixture
was stirred for 16 h at rt. The reaction was quenched with water
and extracted with ethyl acetate. The combined organic phase was
washed with saturated NaHCO3 solution, water, dried (Na2SO4)
and evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography (8→10% EtOAc in
petroleum ether) to afford the diene 7 (673 mg, 78%) as a light
yellow oil. [a]2D5 = +9.6 (c 1.0, CHCl3). IR (CHCl3): 2961, 2935,
2873, 1735, 1613, 1514, 1465, 1249, 910 cm-1. 1H NMR (200 MHz,
CDCl3): d 0.88 (t, J = 7.3 Hz, 3H), 1.20–1.34 (m, 2H), 1.36 (s, 3H),
1.48 (s, 3H), 1.55–1.67 (m, 2H), 1.79–1.91 (m, 2H), 2.32 (d, J =
8.4 Hz, 1H) 2.36 (dd, J = 0.9, 8.8 Hz, 1H) 3.70–3.80 (m, 4H), 4.16
(dd, J = 6.5, 7.4 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 4.52 (d, J =
11.3 Hz, 1H), 4.60 (ddt, J = 0.9, 6.4, 7.8 Hz, 1H), 4.91 (dt, J =
4.0, 7.4 Hz, 1H), 5.17–5.36 (m, 4H), 5.64–5.74 (m, 1H), 5.75–5.84
(m, 1H), 6.88 (br. d, J = 8.6 Hz, 2H), 7.24 (br. d, J = 8.6 Hz, 2H).
13C NMR (50 MHz, CDCl3): d 14.0 (q), 17.9 (t), 25.2 (q), 27.5 (q),
30.3 (t), 33.3 (t), 55.2 (q), 69.8 (t), 71.6 (d), 78.4 (d), 78.8 (d), 79.0
(d), 108.7 (s), 113.7 (2C, d), 117.6 (t), 118.5 (t), 129.3 (d), 130.5
(s), 133.2 (d), 138.3 (d), 159.1 (s), 172.5 (s) ppm. ESI-MS m/z:
455.6 (100%, [M + Na]+), 471.5 (18.5%, [M + K]+). Anal. Calcd
for C25H36O6: C, 69.42; H, 8.39; Found: C, 69.31; H, 8.42%.
1,2-Dideoxy-2,3-O-isopropylidene-4,5-anhydro-D-ribo-hex-1-
enitol (19)
To a solution of 18 (8.52 g, 24.9 mmol) in methanol (75 mL),
solid K2CO3 (10.32 g, 74.7 mmol) was added at rt and stirred
for 10 h. The solids were removed by filtration. The filtrate was
diluted with water and extracted with diethyl ether (3 ¥ 75 mL).
The combined organic extract was washed with water, dried
(Na2SO4) and concentrated under reduced pressure. The residue
thus obtained was purified by column chromatography to afford
19 (3.30 g, 78%) as a colorless oil. [a]2D5: +18.8 (c 1, CHCl3). IR
(CHCl3): 2991, 2930, 1601, 1383, 1253, 1217, 1042, 872 cm-1. 1H
NMR (200 MHz, CDCl3): d 1.36 (s, 3H), 1.50 (s, 3H), 2.66 (dd,
J = 2.5, 5.0 Hz, 1H), 2.81 (dd, J = 3.9, 5.0 Hz, 1H), 2.94 (ddd,
J = 2.6, 3.9, 7.2 Hz, 1H), 3.74 (dd, J = 6.5, 7.2 Hz, 1H), 4.72
(tt, J = 1.0, 6.7 Hz, 1H), 5.34 (ddd, J = 1.0, 1.6, 10.4 Hz, 1H),
5.46 (br. dt, J = 1.4, 17.1 Hz, 1H), 5.98 (ddd, J = 6.8, 10.4,
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Compound 20
N,N-diisopropylethylamine (0.83 mL, 4.79 mmol) were added and
the mixture was stirred for 2 h at ambient temperature. After
completion of mixed anhydride formation as indicated by TLC,
a solution of alcohol 9 (192 mg, 0.96 mmol) in THF (2 mL)
was introduced and the contents were stirred for 16 h at rt. The
reaction mixture was quenched with cold water and extracted
with ethyl acetate. The combined organic phase was washed with
aq. NaHCO3 solution and water, dried (Na2SO4) and evaporated
under reduced pressure. The crude product was purified by silica
gel column chromatography (8→10% EtOAc in petroleum ether)
to procure epi-7 (348 mg, 84%) as a light yellow oil. [a]2D5: -2.8
(c 1.4, CHCl3). IR (CHCl3): 2932, 2872, 1737, 1644, 1613, 1514,
1464, 1442, 1372, 1301, 1172, 1067, 1037, 928, 872, 821 cm-1. 1H
NMR (200 MHz, CDCl3): d 0.89 (t, J = 7.2 Hz, 3H), 1.23–1.36
(m, 2H), 1.36 (s, 3H), 1.48 (s, 3H), 1.56–1.71 (m, 2H), 1.77–1.96
(m, 2H), 2.19–2.48 (m, 2H), 3.70–3.79 (m, 1H), 3.79 (s, 3H), 4.16
(dd, J = 6.6, 7.4 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.52 (d, J =
11.4 Hz, 1H), 4.59 (ddt, J = 1.0, 6.7, 7.4 Hz, 1H), 4.91 (dt, J =
4.0, 7.4 Hz, 1H), 5.16–5.23 (m, 2H), 5.26–5.36 (m, 2H), 5.63–5.88
(m, 2H), 6.87 (br. d, J = 8.6 Hz, 2H), 7.24 (br. d, J = 8.6, 2H).
13C NMR (50 MHz, CDCl3): d 14.0 (q), 17.8 (t), 25.1 (q), 27.4 (q),
30.3 (t 2C), 33.3 (t), 55.2 (q), 69.7 (t), 71.6 (d), 78.3 (d), 78.7 (d),
79.0 (d), 108.7 (s), 113.7 (d), 117.6 (t), 118.3 (t), 129.2 (d), 130.5
(s), 133.2 (d), 138.3 (d), 159.1 (s), 172.4 (s) ppm. Anal. Calcd for
C25H36O6: C, 69.42; H, 8.39; Found: C, 69.31; H, 8.41%.
A suspension of 7 (400 mg, 0.9 mmol) and DDQ (600 mg,
2.6 mmol) in CH2Cl2–H2O (50 mL, 18 : 1) was stirred for 3 h
at rt. The reaction mixture was quenched with aqueous NaHCO3
solution and partitioned between water and CH2Cl2. The aqueous
layer was extracted with CH2Cl2 and the combined organic layer
was dried (Na2SO4) and concentrated. The residue was purified
by silica gel chromatography (25% EtOAc in petroleum ether) to
afford 20 (233 mg, 81%) as a colourless oil. [a]2D5 = +29.4 (c 1.0,
CHCl3). IR (CHCl3): 3453, 2962, 2875, 1732, 1645, 1382, 1217,
1066, 929 cm-1. 1H NMR (200 MHz, CDCl3): d 0.88 (t, J = 7.3 Hz,
3H), 1.18–1.31 (m, 2H), 1.35 (br. s, 3H), 1.46 (br. s, 3H), 1.56–1.71
(m, 2H), 1.74–1.94 (m, 2H), 2.39 (br. dd, J = 2.7, 7.3 Hz, 1H), 2.35
(br. dd, J = 1.5, 7.3 Hz, 1H), 4.15 (d, J = 6.6 Hz, 1H), 4.19 (d, J =
6.6 Hz, 1H), 4.59 (ddt, J = 1.0, 6.6, 7.4 Hz, 1H), 4.91 (dt, J = 4.0,
7.3 Hz, 1H), 5.13 (dt, J = 1.3, 10.4 Hz, 1H), 5.21 (ddd, J = 0.9,
1.7,10.4 Hz, 1H), 5.25 (br. dt, J = 1.4, 7.2 Hz, 1H), 5.33 (br. ddd,
J = 1.1, 1.7, 15.8 Hz, 1H), 5.70–5.92 (m, 2H). 13C NMR (50 MHz,
CDCl3): d 14.0 (q), 17.9 (t), 25.2 (q), 27.5 (q), 30.3 (t), 31.4 (t), 33.3
(t), 71.9 (d), 72.0 (d), 78.3 (d), 78.8 (d), 108.8 (s), 115.1 (t), 118.5
(t), 133.1 (d), 140.3 (d), 172.9 (s) ppm. ESI-MS m/z: 335.4 (100%,
[M + Na]+), 351.4 (13.2%, [M + K]+). Anal. Calcd for C17H28O5:
C, 65.36; H, 9.03; Found: C, 65.19; H, 9.29%.
Stagonolide B
To a solution of diene 20 (50 mg, 0.16 mmol) in dry dichloroethane
(20 mL), 2nd gen. Grubbs’ catalyst (35 mg, 0.04 mmol) was
added and the mixture was degassed under an argon atmosphere
thoroughly. The reaction mixture was refluxed for 24 h and
the solvent was removed under reduced pressure. The residue
was purified by flash column chromatography (30% EtOAc in
petroleum ether) giving impure macrolide (25 mg) as a colorless
liquid. The above compound (25 mg) was suspended at 0 ◦C in TFA
(2 mL) and stirred for 1 h. The reaction mixture was concentrated
under reduced pressure and the residue was purified by column
chromatography (70→100% EtOAc in petroleum ether) to obtain
the 2 as a viscous liquid (15 mg, 39%). [a]2D5 = +27.1 (c 0.9, CHCl3);
Lit.9a [a]D25 = +20 (c 0.1, CHCl3). IR (CHCl3): 3409, 2927, 1729,
Compound 21
A solution of diene epi-7 (70 mg, 0.16 mmol) and 2nd gen.
Grubbs’ catalyst (14 mg, 0.016 mmol) in dry toluene (20 ml) was
degassed with argon thoroughly and heated at 80 ◦C for 6 h.
The volatiles were removed and the residue was purified by flash
chromatography to afford 21 (45 mg, 69%) as a colourless liquid.
[a]2D5 = -9.0 (c 0.6, CHCl3). IR (CHCl3): 3018, 2959, 2924, 2851,
1725, 1611, 1465, 1215, 1162, 1114, 1035, 820 cm-1. H NMR
1
(200 MHz, CDCl3): d 0.89 (t, J = 7.2, 3H), 1.21–1.34 (m, 2H),
1.39 (s, 3H), 1.51–1.68 (m, 2H), 1.55 (s, 3H), 1.71–1.76 (m, 1H),
1.94–2.08 (m, 2H), 2.26–2.36 (m, 1H), 3.79 (s, 3H), 3.81 (dd, J =
4.6, 8.5 Hz, 1H), 3.95 (dd, J = 4.6, 10.1 Hz, 1H), 4.27 (d, J =
11.5 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.71 (ddd, J = 1.6, 3.0,
4.6 Hz, 1H), 4.94 (ddd, J = 2.6, 8.3, 10.1 Hz, 1H), 5.66 (ddd, J =
1.6, 8.3, 15.9 Hz, 1H), 5.84 (dd, J = 3.1, 15.9 Hz, 1H), 6.85 (d,
J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d 13.8 (q), 17.8 (t), 26.3 (q), 28.4 (q), 31.2 (t), 31.8(t), 34.2
(t), 55.2 (q), 69.8 (t), 70.6 (d), 75.9 (d), 78.6 (d), 81.6 (d), 109.3 (s),
113.8 (d), 127.4 (d), 128.2 (d), 129.3 (d), 130.5 (s), 159.1 (s), 174.9
(s). ESI-MS m/z: 405.5 (10%, [M + H]+), 427.5 (100%, [M + Na]+.
Anal. Calcd for C23H32O6: C, 68.29; H, 7.97; Found: C, 68.19; H,
8.01%.
1
1560 cm-1. H NMR (400 MHz, CDCl3): d 0.90 (t, J = 7.4 Hz,
3H), 1.23–1.30 (m, 1H), 1.32–1.42 (m, 1H), 1.57 (ddq, J = 4.9,
9.8, 14.3 Hz, 1H), 1.64 (br. s, 1H, –OH), 1.82–1.92 (m, 2H), 2.07
(br. ddd, J = 2.6, 5.5, 14.3 Hz, 1H), 2.12 (br. dt, J = 2.6, 14.4 Hz,
1H), 2.24 (br. d, J = 8.4 Hz, 1H, C7–OH), 2.44 (br. s, 1H, –OH),
2.45 (br. dt, J = 1.8, 14.4 Hz, decouple at 1.9→t, J = 13.4, 1H),
3.57 (br. t, J = 8.5 Hz, decouple at 2.48→dd, J = 2.6, 9.9 Hz,
1H), 4.47–4.53 (br. s, decouple at 2.29→dt, J = 2.6, 4.6 Hz, 1H),
4.59–4.64 (br. s, 1H), 4.94 (dt, J = 2.5, 9.6 Hz, decouple at 1.90→t,
J = 9.5 Hz, 1H), 5.63 (dt, J = 2.7, 16.1 Hz, 1H), 5.99 (dt, J = 1.7,
16.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 13.9 (q), 18.0 (t),
27.8 (t), 31.6 (t), 33.6 (t), 68.6 (d), 70.2 (d), 73.6 (d), 73.6 (d), 127.1
(d), 127.2 (d), 176.5 (s). ESI-MS m/z: 267.2 (100%, [M + Na]+).
Anal. Calcd for C12H20O5: C, 59.00; H, 8.25; Found: C, 59.22; H,
8.10%.
4-epi-Stagonolide (epi-2)
A solution of compound 21 (21 mg, 0.05 mmol) and TFA (2 mL)
was stirred at 0 ◦C for 1 h. The reaction mixture was concentrated
under reduced pressure and the residue was purified by column
chromatography (70→100% EtOAc in petroleum ether) to procure
Diene epi-7
◦
epi-2 as a colorless solid (11 mg, 87%). MP: 185–187 C. [a]2D5:
To a solution of acid (S)-8 (240 mg, 0.96 mmol) in dry THF (5 mL),
2,4,6-trichlorobenzyl chloride (0.22 mL, 1.44 mmol) followed by
+11.3 (c 0.3, CH3OH). IR (CHCl3): 3390, 2921, 1730, 1563 cm-1.
1H NMR (500 MHz, CD3OD): d 0.91 (t, J = 7.4 Hz, 3H),
404 | Org. Biomol. Chem., 2010, 8, 398–406
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1.22–1.36 (m, 2H), 1.43–1.51 (m, 1H), 1.76–1.85 (m, 2H), 1.89–
1.94 (m, 1H), 2.03 (dt, J = 2.2, 13.5 Hz, 1H), 2.26 (ddd, J = 2.4,
6.3, 13.5 Hz, 1H), 3.50 (dd, J = 2.5, 9.7 Hz, 1H), 4.06 (br. ddd, J =
4.7, 9.3, 10.8 Hz, 1H), 4.38 (br. dd, J = 2.3, 4.6 Hz, 1H), 5.13 (dt,
J = 2.7, 9.6 Hz, 1H), 5.50 (ddd, J = 2.3, 9.3, 15.6 Hz, 1H), 5.77
(dd, J = 2.2, 15.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): d 14.4
(q), 18.9 (t), 32.5 (t), 33.9 (t), 35.1 (t), 71.9 (d), 73.6 (d), 74.6 (d),
75.9 (d), 128.2 (d), 133.5 (d), 176.3 (s) ppm. ESI-MS m/z: 245.2
(100%, [M + H]+). Anal. Calcd for C12H20O5: C, 59.00; H, 8.25;
Found: C, 58.85; H, 8.26%.
New Delhi) and Council of Scientific & Industrial Research
(CSIR, New Delhi) in the form of research fellowships respectively
to AGG and to MAM is gratefully acknowledged.
Notes and references
1 A. Fu¨rstner and M. Thomas, Synlett, 1997, 1010–1012.
2 H. M. C. Ferraz, F. I. Bombonato and L. S. Longo Jr, Synthesis, 2007,
3261–3285 and references cited therein.
3 Recent reviews: (a) A. Deiters and S. F. Martin, Chem. Rev., 2004, 104,
2199–2238; (b) T. Gaich and J. Mulzer, Curr. Top. Med. Chem., 2005,
5, 1473–1494; (c) J. C. Conrad and D. E. Fogg, Curr. Org. Chem., 2006,
10, 185–202; (d) A. Gradillas and J. Pe´rez-Castells, Angew. Chem., Int.
Ed., 2006, 45, 6086–6101; (e) V. B. Riatto, R. A. Pilli and M. M. Victor,
Tetrahedron, 2008, 64, 2279–2300; (f) F. Boeda, H. Clavier and S. P.
Nolan, Chem. Commun., 2008, 2726–2740; (g) J. W. Herndon, Coord.
Chem. Rev., 2009, 253, 86–179.
4 (a) A. Fu¨rstner and K. Radkowski, Chem. Commun., 2001, 671–672;
(b) A. Fu¨rstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann
and R. Mynott, J. Am. Chem. Soc., 2002, 124, 7061–7069.
5 C. V. Ramana, T. P. Khaladkar, S. Chatterjee and M. K. Gurjar, J. Org.
Chem., 2008, 73, 3817–3822.
6 For the synthesis of nonenolides with 1,4-cis-diol configuration see:
(a) D. K. Mohapatra, D. K. Ramesh, M. A. Giardello, M. S.
Chorghade, M. K. Gurjar and R. H. Grubbs, Tetrahedron Lett.,
2007, 48, 2621–2625; (b) S. Ghosh and R. V. Rao, Tetrahedron Lett.,
2007, 48, 6937–6940; (c) P. Gupta and P. Kumar, Eur. J. Org. Chem.,
2008, 1195–1202; (d) J. Liu, L. Zhang, J. He, L. He, B. Ma, X. Pan
and X. She, Tetrahedron: Asymmetry, 2008, 19, 906–911. During this
manuscript revision, the syntheses of the nonenolides decarestrictine
C1 and staganolide C, with 1,4-trans-diol configuration were reported:
(e) D. K. Mohapatra, U. Dash, P. R. Naidu and J. S. Yadav, Synlett,
2009, 2129–2132; (f) D. K. Mohapatra, G. Sahoo, D. K. Ramesh, J. S.
Rao and G. N. Sastry, Tetrahedron Lett., 2009, 50, 5636–5639.
7 For the construction of 10-membered carbocycles with the 2-ene-1,4-
diol unit see: (a) L. Caggiano, D. Castoldi, R. Beumer, P. Bayo´n, J.
Telser and C. Gennari, Tetrahedron Lett., 2003, 44, 7913–7919; (b) D.
Castoldi, L. Caggiano, L. Panigada, O. Sharon, A. M. Costa and C.
Gennari, Chem.–Eur. J., 2006, 12, 51–62; (c) C. Gennari, D. Castoldi
and O. Sharon, Pure Appl. Chem., 2007, 79, 173–180.
Diene epi-20
To a solution of epi-7 (100 mg, 0.23 mmol) in CH2Cl2–H2O (15 mL,
18 : 1) DDQ (157 mg, 0.69 mmol) was added and stirred for 3 h
at rt. The reaction mixture was quenched with aqueous NaHCO3
solution and partitioned between water and CH2Cl2. The aqueous
layer was extracted with CH2Cl2 and the combined organic layer
was dried (Na2SO4) and concentrated. The residue was purified
by silica gel chromatography (25% EtOAc in petroleum ether)
to procure epi-20 (60 mg, 86%) as a colorless oil. [a]2D5 = +30.5
(c 1.0, CHCl3). IR (CHCl3): 3453, 2961, 2864, 1732, 1643, 1388,
1215, 1061, 924 cm-1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J =
7.4 Hz, 3H), 1.23–1.34 (m, 2H), 1.35 (br. s, 3H), 1.47 (br. s, 3H),
1.58–1.71 (m, 2H), 1.74–1.89 (m, 2H), 2.35 (br. dd, J = 2.7, 7.4 Hz,
1H), 2.30–2.43 (m, 2H), 4.13 (br. dd, J = 6.0 Hz, 1H), 4.17 (dd,
J = 6.7, 7.4 Hz, 1H), 4.59 (br. t, J = 7.2 Hz, 1H), 4.91 (dt, J =
3.5, 7.6 Hz, 1H), 5.13 (br. dt, J = 1.2, 10.5 Hz, 1H), 5.18–5.26
(m, 2H), 5.32 (br. dt, J = 1.2, 17.0 Hz, 1H), 5.74–5.88 (m, 2H).
13C NMR (100 MHz, CDCl3): d 14.0 (q), 17.9 (t), 25.2 (q), 27.5
(q), 30.3 (t), 31.4 (t), 33.3 (t), 71.9 (d), 72.1 (d), 78.3 (d), 78.8 (d),
108.8 (s), 115.1 (t), 118.6 (t), 133.1 (d), 140.3 (d), 173.0 (s) ppm.
ESI-MS m/z: 335.2 (100%, [M + Na]+). Anal. Calcd for C17H28O5:
C, 65.36; H, 9.03; Found: C, 65.24; H, 9.15%.
8 O. Yuzikhin, G. Mitina and A. Berestetskiy, J. Agric. Food Chem., 2007,
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Cimmino, A. Berestetskiy, A. Andolfi and A. Motta, J. Nat. Prod.,
2008, 71, 1897–1901.
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Murty and V. J. Rao, Bioorg. Chem., 2009, 37, 46–51.
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2543–2549; (b) I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa,
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and L. S. Jeong, J. Org. Chem., 2004, 69, 2634–2636.
RCM of diene epi-20
To a degassed solution of diene epi-20 (40 mg, 0.12 mmol) and
2nd gen. Grubbs’ catalyst (11 mg, 0.012 mmol) in dry DCM
(40 mL) was heated to reflux under argon atmosphere for 6 h and
concentrated. The residue was purified by flash chromatography
to furnish 22 (32 mg, 89%) as colourless semisolid. [a]2D5 = +55.1
(c 0.5, CHCl3). IR (CHCl3): 3467, 3020, 1732, 1542, 1452, 1349,
1216, 1046 cm-1. 1H NMR (400 MHz, CDCl3): d 0.9 (t, J = 7.3,
3H), 1.26–1.35 (m, 2H), 1.36 (s, 3H), 1.41–1.50 (m, 2H), 1.54 (s,
3H), 1.70–1.78 (m, 1H), 1.98–2.05 (m, 2H), 2.29–2.35 (m, 1H),
3.95 (dd, J = 4.7, 10.1 Hz, 1H), 4.13–4.20 (m, 1H), 4.68 (br. ddd,
1.9, 3.1, 4.7 Hz, 1H), 4.92 (ddd, J = 2.7, 8.9, 10.1 Hz, 1H), 5.64
(ddd, J = 1.7, 8.6, 15.9 Hz, 1H), 5.81 (dd, J = 3.3, 15.9 Hz, 1H).
13C NMR (100 MHz, CDCl3): d 13.9 (q), 17.8 (t), 26.2 (q), 28.4
(q), 31.2 (t), 33.6 (t), 34.1 (t), 70.8 (d), 75.6 (d), 75.7 (d), 78.6 (d),
109.3 (s), 126.7 (d), 128.1 (d), 175.0 (s) ppm. ESI-MS m/z: 307.1
(100% [M + Na]+). Anal. Calcd for C15H24O5: C, 63.36; H, 8.51;
Found: C, 63.25; H, 8.39%.
17 G. V. M. Sharma, A. S. Chander, K. Krishnudu and P. R. Krishna,
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20 Selected reports that deal with the proximal substituent effects on the
construction of medium rings by RCM: (a) T. R. Hoye and H. Zhao,
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Acknowledgements
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We thank the Department of Science and Technology
(SR/S5/GC-20/2007 and SR/S5/OBP-66/2008) for funding.
Financial support from the University Grants Commission (UGC,
Mitchell, J. A. Parkinson, J. M. Percy and K. Singh, J. Org. Chem.,
2008, 73, 2389–2395; (e) T. Imahori, H. Ojima, Y. Yoshimura and
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The Royal Society of Chemistry 2010
©