Chemo-enzymatic asymmetric total synthesis of stagonolide-C

Article abstract of DOI:10.1016/j.tetasy.2009.10.007

The naturally occurring phytotoxic noneolide stagonolide-C has been synthesized by a chemo-enzymatic approach. Two key intermediates have been synthesized by applying a metal-enzyme combined DKR (dynamic kinetic resolution) strategy, followed by RCM (ring

Full text of DOI:10.1016/j.tetasy.2009.10.007

Tetrahedron: Asymmetry 20 (2009) 2622–2628
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemo-enzymatic asymmetric total synthesis of stagonolide-C
*
Nandan Jana, Tridib Mahapatra, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The naturally occurring phytotoxic noneolide stagonolide-C has been synthesized by a chemo-enzymatic
approach. Two key intermediates have been synthesized by applying a metal–enzyme combined DKR
(dynamic kinetic resolution) strategy, followed by RCM (ring-closing metathesis) to afford the target
compound in an efficient way.
Received 9 September 2009
Accepted 7 October 2009
Available online 26 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
very good synthetic targets. In this article we report the total
synthesis of such a noneolide stagonolide-C. During the course of
Naturally occurring 10-membered ring lactones (noneolides)
from fungal metabolites present a wide variety of bioactive sub-
stances. Among them, modiolide A–B was isolated by Kobayashi
and co-workers1 and shown to have antibacterial and antifungal
activities. Macrolides, particularly lactones with medium-sized
rings (8–10-membered), have continued to attract the attention
of both biologists and chemists during recent years,2 due to the
interesting biological properties and scarce availability of macro-
lides. A few examples, in particular of 10-membered-ring-contain-
ing macrolides that display potent biological activity, are
putaminoxin and pinolidoxin.3 The nonenolide (5S,9R)-5-hydro-
xy-9-methyl-6-nonen-9-olide, a diastereomer of aspinolide, is
one such example, and has been isolated from Stagonospora cirsii.
S. cirsii, a fungal pathogen isolated from Cirsium arvense and pro-
posed as a potential mycoherbicide of this perennial noxious weed,
produces phytotoxic metabolites in liquid and solid cultures.4 Re-
cently, the main metabolite, stagonolide, with interesting phyto-
our study Mohapatra et al. reported the first asymmetric synthesis
of stagonolide-C.5
2. Results and discussion
Retrosynthetic analysis of the target molecule stagonolide-C is
shown in Scheme 2.
The internal double bond between C5–C6 was thought to be a
crucial disconnection as it can be reconnected through a RCM reac-
tion. The crucial ester linkage between C1–C9 is planned to be con-
structed by an esterification reaction of a properly substituted acid
and alcohol. The required acid and the alcohol are constructed
from a more easily available starting material. Two of the stereo-
centers in the parent molecule, for example, C4 and C9 are to be
constructed by applying a metal–enzyme combined DKR strategy.6
2.1. Synthesis of the 4-methoxy-benzyloxy-hex-5-enoic acid
fragment
toxic properties, was isolated from
a liquid culture and
characterized as a new nonenolide. Five new nonenolides, named
stagonolides B–F, were isolated and characterized using spectro-
scopic methods. When tested by a leaf disk puncture assay at a
concentration of 1 mg/mL, these compounds showed no toxicity
to C. arvense and Sonchus arvensis, whereas stagonolide was highly
toxic. A further four nonenolides were isolated and characterized
by spectroscopy. Three were new compounds which were named
stagonolides G–I, and the fourth was identified as modiolide A, pre-
viously isolated from Paraphaeosphaeria sp., which is a fungus sep-
arated from the horse mussel (Scheme 1).
The synthesis starts from 1,4-butane-diol. Selective monopro-
tection with TBS-Cl (tert-butyldimethyl silyl chloride) by the
Mc-Dougals protocol7 yielded the mono TBS-protected ether 1 in
90%. Swern oxidation followed by addition of vinyl magnesium
bromide at ꢀ78 °C afforded the alcohol 3 in 82% yield from alde-
hyde 2. DKR of the secondary alcohol functionality in compound
3 was achieved by coupling enzyme-catalyzed transesterification
reaction with a metal-catalyzed (ruthenium-based catalyst shown
in Scheme 3) racemization method as reported by Kim et al.8
Isopropenyl acetate was used as the acyl donor in the DKR reaction.
The DKR reaction is highly efficient for compound 3 as it yields the
corresponding acetate 4 in 90% and with excellent enantioselection
(ee = 99%).9 The acetate functionality was removed by treatment
with K2CO3 in MeOH to yield enantiomerically pure 5 in 94%. The
alcohol functionality in 5 was protected as its PMB ether by treat-
ing with PMB-imidate10 in the presence of a catalytic amount of
All of the noneolides shown in Scheme 1 possess interesting
structural features, as they are compact, they contain a properly
placed olefinic moiety with well-defined geometry and the pres-
ence of stereochemically pure hydroxy appendages makes them
* Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.007

N. Jana et al. / Tetrahedron: Asymmetry 20 (2009) 2622–2628
2623
O
O
O
O
O
O
O
O
O
O
HO
OH
OH
OH
OH
Modiolide-A
Curvulide-B2
Curvulide-B1
Modiolide-B
OH
OH
OH
OH
OH
OH
O
O
O
O
O
OH
O
O
nPr
O
O
Stagonolide-C
Stagonolide-B
OH
Stagonolide-E
Stagonolide-D
O
OH
OH
O
O
O
O
O
HO
OH
OH
O
O
O
Stagonolide-G
Stagonolide-I
Stagonolide-H
Stagonolide-F
Scheme 1. Naturally occurring small ring macrolides.
RCM
OH
OP
OH
OP
OH
OH
4
6
9
3
2
+
7
8
5
O
HO
1
O
O
O
OH
O
Stagonolide C
P = 4-methoxybenzyl (PMB)
OH
OH
HO
OH
Scheme 2. Retrosynthetic analysis of stagonolide-C.
CSA (camphor sulfonic acid) to yield compound 6. Compound 6
when treated with PPTS (pyridinium para-toluene sulfonate)/
MeOH led to removal of the TBS group11 and afforded the com-
pound 7 in 88% yield. Oxidation of the primary alcohol functional-
ity with PDC (pyridinium dichromate) in DMF afforded the
corresponding acid 8 in 72% yield (Scheme 3).12 The same interme-
diate 8 was synthesized by Mohapatra et al. in eleven steps starting
from 1,4-butane diol, whereas we have synthesized in eight steps
starting from 1,4-butane diol in 29% overall yield.
presence of isopropenyl acetate as an acyl donor to afford the cor-
responding acetate 10 in 92% yield with excellent enantioselection
(ee = 98%).13 The acetate group in 10 was deprotected with K2CO3/
MeOH to afford enantiomerically pure 11 in 90% yield. The second-
ary hydroxyl group in 11 was protected as its TBDPS (tert-butyldi-
phenylsilyl) ether by treatment with imidazole/TBDPS-Cl to afford
compound 12 in 95% yield. Removal of the PMB group was success-
fully achieved with DDQ14 to afford compound 13 in 86% yield.
Oxidation under Swern condition15 afforded the aldehyde 14 in
92% yield. Vinylmagnesium bromide addition on compound 14
afforded the two diastereomers 15 and 16 in 1:1 ratio, which can
be separated by silica gel chromatography. The anti-stereochemis-
try between the two hydroxyl functionalities was established by
Rychnovsky’s method.16 Thus, under treatment with TBAF (tetra-
n-butyl ammonium fluoride) compounds 15 and 16 afforded the
respective diols 17 and 18. Reaction with 2,2-DMP (2,2-dimethoxy-
propane) in the presence of PPTS afforded the respective aceto-
nides17 19 and 20. 13C NMR analysis of 19 and 20 established the
relative stereochemistry of the two hydroxyl functionalities unam-
2.2. Synthesis of the (2R,4S)-4-methoxy-benzyloxy-hex-5-ene-
2-ol fragment
The synthesis starts from the commercially available racemic
1,3-butane-diol. The primary alcohol functionality was selectively
protected as its PMB ether by treatment with NaH and PMB–Br
in the presence of a catalytic amount of TBAI (tetra-n-butyl ammo-
nium iodide) to yield the compound 9 in 80% yield. Metal–enzyme-
combined DKR reaction was applied to compound 9 in the

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N. Jana et al. / Tetrahedron: Asymmetry 20 (2009) 2622–2628
O
a
OH
d
OTBS
b
OTBS
HO
c
HO
H
2
1
OPMB
OPMB
OH
OR
g
h
O
8
7
OH
OH
OTBS
OTBS
Ph
3
R = Ac; 4
R = H; 5
e
f
Ph
NHiPr
DKR catalyst
R = PMB; 6
Ph
Cl
Ph
CO
Ru
CO
Scheme 3. Reagents and conditions: (a) NaH TBS-Cl, 90%; (b) (COCl)2, DMSO, Et3N, ꢀ78 °C, 88%; (c) CH2@CH–MgBr, ꢀ78 °C, 82%; (d) CAL-B, isopropenyl acetate,
chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-tetraphenylcyclopentadienyl) ruthenium(II), K2CO3, KOtBu 90%; (e) K2CO3, MeOH, 94%; (f) PMBO–(C@NH)–CCl3, CSA, 85%; (g)
PPTS, MeOH, 88%; (h) PDC, DMF, 72%.
biguously. The unwanted syn-diastereomer 16 was converted to
the required anti-diastereomer 15 by Mitsunobu inversion fol-
lowed by removal of the benzoate group under basic conditions.
The secondary hydroxyl group in 15 was protected as its PMB ether
by the treatment of PMB-imidate in the presence of catalytic CSA to
afford compound 21 in 82% yield. Deprotection of TBDPS group
was finally achieved by treatment with TBAF to afford the desired
compound 22 in 90% yield.18 The same intermediate 22 was also
synthesized by Mohapatra et al. in twelve steps starting from
2.3. Coupling of fragment 8 and 22 for the total synthesis of
stagonolide-C
After successful construction of both the required fragments 8
and 22, the remaining task was to couple the two fragments fol-
lowed by a RCM strategy. The coupling of the two fragments was
successfully achieved by treating acid 8 with EEDQ (2-ethoxy-1-
ethoxycarbonyl-1,2-dihydroquinoline) to prepare the mixed anhy-
dride, followed by the addition of alcohol 22 to afford the coupled
ester 23 in 90% yield.19 The final RCM reaction seems to be crucial
and problematic as depicted by Mohapatra et al. After numerous
L-malic acid, whereas we have synthesized 22 from ( )-1,3-butane-
diol in ten steps in 28% overall yield (Scheme 4).
OH
OH
OH
OAc
a
b
c
d
OH
OPMB
OPMB
OPMB
g
9
11
10
OTBDPS
OTBDPS
OH
e
f
OTBDPS
OH
+
CHO
OH
OPMB
PO
h
PO
13
14
12
P = TBDPS
15
16
15
δ = 30.29, 19.82 ppm
δ = 25.72, 25.00 ppm
δ = 100.23 ppm
δ = 98.59 ppm
O
O
O
O
OH
OH
OH
OH
+
i
j
+
20
19
18
17
OH
OPMB
OPMB
k
l
TBDPSO
HO
TBDPSO
15
21
22
Scheme 4. Reagents and conditions: (a) NaH, PMB–Br, TBAI (cat), 80%; (b) CAL-B, isopropenylacetate, chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-tetraphenylcyclopen-
tadienyl ruthenium(II), K2CO3, KOtBu, 92%; (c) K2CO3, MeOH, 90%; (d) imidazole, TBDPS-Cl, 95%; (e) DDQ, DCM/H2O (19:1), 86%; (f) (COCl)2, DMSO, Et3N, ꢀ78 °C, 92%; (g)
CH2@CH–MgBr, ꢀ78 °C, 80%; (h) TPP (triphenylphosphine), DIAD (diisopropyl azodicarboxylate), PhCO2H, NaOH, 90% in two steps; (i) TBAF, THF, 88%; (j) 2,2-DMP, PPTS, 86%;
(k) PMBO–(C@NH)–CCl3, CSA, 82%; (l) TBAF, THF, 90%.

N. Jana et al. / Tetrahedron: Asymmetry 20 (2009) 2622–2628
2625
OPMB
OPMB
OPMB
OH
OPMB
OPMB
OPMB
a
+
X
HO
O
O
O
O
O
22
23
8
b
OH
OH
OH
OH
c
O
O
O
Stagonolide-C
O
24
Scheme 5. Reagents and conditions: (a) EEDQ, THF, 92%; (b) DDQ, DCM/H2O (19:1), 85%; (c) Grubbs-II, DCM, 66%.
conditions were tried with Grubbs-I and Grubbs-II in different sol-
vents, for example, DCM, benzene, and toluene, the final outcome
was the same in all the cases. Either inseparable mixtures of vari-
ous compounds were obtained or the starting material had decom-
posed during the course of the reaction. Finally deprotection of the
PMB functionality was achieved by treating compound 23 with
DDQ to afford the diol 24 in 85% yield. Compound 24 upon treat-
ment with Grubbs-second generation catalyst afforded the target
molecule Stagonolide-C (Scheme 5).
dH and dC for 1H and 13C, respectively. Mass spectral analysis was
performed in the Central Research Facility (CRF), IIT-Kharagpur.
Optical rotations were measured on a JASCO P-1020 digital polar-
imeter. Chiral HPLC was performed using Chiral AS-H, OJ-H and
OD-H column (0.46 ꢁ 25 cm, Daicel industries) with Shimadzu
Prominence LC-20AT chromatograph coupled with UV–vis detector
(254 nm). Eluting solvent used was a differing ratio of hexane and
2-propanol.
4.2. 4-(tert-Butyl-dimethyl-silanyloxy)-butan-1-ol 1
3. Conclusion
The mono TBS-protected ether was prepared as reported in the
literature20 and provided comparable spectral characteristic
values.
In conclusion we have described an efficient chemo-enzymatic
asymmetric total synthesis of naturally occurring noneolide stag-
onilide-C. A metal–enzyme combined DKR strategy was success-
fully applied to access two advanced intermediates 8 and 22 in
an efficient way. Coupling of these two intermediates followed
by ring-closing metathesis with Grubbs-second generation catalyst
afforded the target molecule. Synthetic studies directed towards
several structurally related noneolides are currently in progress
in our laboratory.
4.3. 4-(tert-Butyl-dimethyl-silanyloxy)-butyraldehyde 2
Aldehyde 2 was prepared as reported in the literature20 and
provides comparable spectral characteristic values.
4.4. 6-(tert-Butyl-dimethyl-silanyloxy)-hex-1-en-3-ol 3
Aldehyde 2 (2.5 g, 11.26 mmol) was taken in 40 mL of anhy-
drous THF. Solution of vinylmagnesium bromide (1 M, 15 mL,
15 mmol) was added to it at ꢀ78 °C. The reaction mixture was kept
at the same temperature for 1 h, after which time saturated NH4Cl
solution was added to it. The solution was extracted with EtOAc,
and the organic layer was washed with water and brine. The organ-
ic layer was dried (MgSO4) and evaporated. Purification by silica
gel chromatography (3:1, hexane/EtOAc) afforded the alcohol 3
in 82% yield.
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethylether were distilled from sodiumbenzophenone ketyl.
Dichloromethane (DCM), dimethylformamide (DMF) and dimeth-
ylsulfoxide (DMSO) were distilled from calcium hydride. Diiso-
propylether (DIPE) was refluxed over P2O5 and distilled prior to
use. Vinyl acetate and isopropenyl acetate were freshly distilled
prior to use. CAL-B (Candida antartica lipase-B, Novozym-435,
immobilized on acrylic resin) was obtained from Sigma and used
as obtained. Reactions were monitored by thin-layer chromatogra-
phy (TLC) carried out on 0.25 mm silica gel plates (Merck) with UV
light, ethanolic anisaldehyde and phosphomolybdic acid/heat as
developing agents. Silica gel 100–200 mesh was used for column
chromatography. Yields refer to chromatographically and spectro-
scopically homogeneous materials unless otherwise stated. NMR
spectra were recorded on Bruker 400 MHz spectrometers at 25 °C
in CDCl3 using TMS as the internal standard. Chemical shifts are
shown in d. 13C NMR spectra were recorded with a complete pro-
ton decoupling environment. The chemical shift value is listed as
dH: 5.85 (m, 1H), 5.24 (dd, J = 16.2, 1.8 Hz, 1H), 5.07 (dd,
J = 11.2 Hz, 1.8 Hz, 1H), 4.1 (m, 1H), 3.64 (t, J = 6.0 Hz, 2H), 1.6
(m, 4H), 0.9 (s, 9H), 0.05 (s, 6H).
dC: 141.23, 114.51, 72.8, 63.36, 34.3, 28.71, 25.8, 18.72, ꢀ3.59,
ꢀ4.56.
4.5. Acetic acid (S)-4-(tert-butyl-dimethyl-silanyloxy)-1-vinyl-
butyl ester 4
In a 50 mL round-bottomed flask attached to a grease-free high-
vacuum stopcock, chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-
tetraphenylcyclopentadienyl) ruthenium(II) [DKR catalyst, 84 mg,
0.136 mmol] was taken. The flask was successively charged with
alcohol
3 (0.86 g, 3.4 mmol) in 10 mL dry toluene, Na2CO3
(3.4 mmol), CAL-B (25 mg) and KOtBu (0.17 mmol) followed by

2626
N. Jana et al. / Tetrahedron: Asymmetry 20 (2009) 2622–2628
isopropenyl acetate (5 mmol). The reaction mixture was stirred at
room temperature under argon atmosphere, after which it was
filtered off and the solution was evaporated to afford the crude
acetate 4, which was subsequently purified by silica gel chroma-
tography (10:1, hexane/EtOAc) to afford the pure acetate 4 in
90% yield. dH: 5.77 (m, 1H), 5.278 (d, J = 10.4 Hz, 1H), 5.25–5.14
(m, 2H), 3.61 (t, J = 6.4 Hz, 2H), 2.05 (s, 3H), 1.7–1.5 (m, 4H), 0.9
(s, 9H), 0.06 (s, 6H). dC:170.33, 136.53, 116.62, 74.58, 62.68,
1.75, MeOH). HRMS (+ESI) calcd for
259.1304; found, 259.1301.
C
14H20O3Na (M+Na+):
4.9. (S)-4-(4-Methoxy-benzyloxy)-hex-5-enoic acid 8
Compound 7 (0.4 g, 1.7 mmol) was taken in anhydrous DMF
(10 mL). Pyridinium dichromate (PDC, 3.2 g, 8.5 mmol) was added
to the reaction mixture and the reaction mixture was stirred at
room temperature till all the starting material has been consumed
as indicated by TLC. Water was added to the reaction mixture, the
water layer was extracted thrice with EtOAc (3 ꢁ 25 mL) followed
by washing with an aq KHSO4 solution. The organic solvent was
dried (MgSO4) and evaporated. The crude acid was purified by sil-
ica gel chromatography (1:1, hexane/EtOAc). dH: 7.24 (d, J = 8.4 Hz,
2H), 6.86 (d, J = 8.4 Hz, 2H), 5.73 (m, 1H), 5.25 (m, 2), 4.52 (d,
J = 11.2 Hz, 1H), 4.28 (d, J = 11.2 Hz, 1H), 3.8 (s, 3H), 3.76 (m, 1H),
2.45 (t, J = 7.2 Hz, 2H), 1.94–1.8 (m, 4H). dC: 179.44, 159.06,
138.09, 130.35, 129.35, 117.70, 113.72, 78.76, 69.79, 55.18, 30.07,
30.57, 28.33, 25.94, 21.22, 18.32, ꢀ5.22. ½a D29
¼ ꢀ2:7 (c 1.0, MeOH).
ꢂ
4.6. (S)-6-(tert-Butyl-dimethyl-silanyloxy)-hex-1-en-3-ol 5
The pure acetate 4 (0.45 g, 1.5 mmol) was taken in MeOH fol-
lowed by the addition of K2CO3 (0.213 g, 1.5 mol) and the solution
was stirred at room temperature for 2 h. After this time, the MeOH
was evaporated and the residue was taken in DCM, and washed
successively with water and brine. The organic layer was dried
(MgSO4) and purified through silica gel chromatography (3:1, hex-
ane/EtOAc) to yield the (S)-alcohol 5.
30.01. ½a 2D9
¼ ꢀ19:9 (c 1.0, MeOH).
ꢂ
½
a 2D9
ꢂ
¼ ꢀ32:85 (c 1.0, MeOH).
HRMS (+ESI) calcd for C14H18O4Na (M+Na+): 273.1097; found,
273.1091.
4.7. tert-Butyl-[(S)-4-(4-methoxy-benzyloxy)-hex-5-enyloxy]-
dimethyl-silane 6
4.10. 4-(4-Methoxy-benzyloxy)-butan-2-ol 9
A solution of 4-methoxybenzyl alcohol (2.2 g, 16 mmol) in 15 mL
of ether was added to a suspensionof 65% NaH (0.128 g, 3.2 mmol) in
20 mL of ether at room temperature. The resulting mixture was stir-
red at room temperature for 30 min and cooled to 0 °C. Trichloroace-
tonitrile (TCA, 1.926 mL, 19.2 mmol) was added to it and the
reaction mixture was allowed to warm slowly to room temperature
over 6 h. The solution was evaporated to an orange syrup, which was
dissolved in anhydrous hexane (40 mL) containing a few drops of
MeOH. This suspension was shaken vigorously and filtered through
Celite, and the filtrate was concentrated to afford the crude imidate.
The crude imidate (3.68 g, 13 mmol) was taken in cyclohexane
(20 mL) and a solution of alcohol 5 (1.5 g, 6.52 mmol) in 10 mL of
DCM was added. The resulting solution was cooled to 0 °C and CSA
(0.151 g, 0.652 mmol) was added to it. The reaction mixture was
stirred overnight at room temperature, and a white precipitate of tri-
chloroacetamide developed slowly. The solutionwas filtered off, and
washed with DCM. The filtrate was washed with NaHCO3 solution,
water and brine. Purification by means of silica gel chromatography
9:1 (hexane/EtOAc) yielded compound 6 in 85% yield. dH: 7.25 (d,
J = 7.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 5.73 (m, 1H), 5.23–5.18 (m,
2H), 4.5 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 11.2 Hz, 1H), 3.77 (s, 3H),
3.61 (m, 1H), 3.58 (t, J = 6.4 Hz, 2H), 1.65–1.54 (m, 4H), 0.917 (s,
9H), 0.049 (s, 6H). dC: 159.08, 139.21, 130.93, 129.32, 116.96,
113.76, 80.06, 69.71, 63.07, 55.27, 31.82, 28.72, 26.0, 18.37, ꢀ5.27.
Butane-1,3-diol (10 g, 111 mmol) was taken in 200 mL of dry
THF. Then, NaH (60% dispersion in mineral oil, 3.11 g, 111 mmol)
was added to it portionwise at 0 °C. The reaction mixture was stir-
red at 0 °C for 1 h. Tetrabutylammonium iodide (TBAI, 5 mmol)
was added to it followed by the addition of 4-methoxybenzylbro-
mide. The reaction mixture was stirred for a further 2 h at room
temperature. Water was added carefully to the reaction mixture
to quench any excess of NaH. The reaction mixture was extracted
with a large volume of EtOAc. The organic solution was washed
with water and brine. Evaporation and purification by means of sil-
ica gel chromatography (2.5:1, hexane/EtOAc) afforded the com-
pound 9 in 80% yield.
dH: 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.42 (s, 2H),
3.94 (m, 1H), 3.77 (s, 3H), 3.62 (m, 2H), 1.75–1.65 (m, 2H), 1.15
(d, J = 6.0 Hz, 3H).
dC: 159.20, 129.98, 129.24, 113.78, 72.86, 67.52, 55.20, 38.04,
23.27.
4.11. Acetic acid (R)-3-(4-methoxy-benzyloxy)-1-methyl-propyl
ester 10
In a 100 mL round-bottomed flask attached to a grease free
high vacuum stopcock, chlorodicarbonyl(1-(isopropylamino)-
2,3,4,5-tetraphenylcyclopentadienyl) ruthenium(II) [DKR catalyst,
142 mg, 0.228 mmol] was taken. The flask was successively
charged with alcohol 9 (1.2 g, 5.7 mmol) in 20 mL of dry toluene,
Na2CO3 (5.7 mmol), CAL-B (65 mg) and KOtBu (0.28 mmol) fol-
lowed by isopropenyl acetate (5 mmol). The reaction mixture
was stirred at room temperature under an argon atmosphere, after
which the reaction mixture was filtered off and the solution was
evaporated to afford the crude acetate 10, which was subsequently
purified by silica gel chromatography (7:1, hexane/EtOAc) to afford
the pure acetate 10 in 92% yield. dH: 7.22 (d, J = 8.4 Hz, 2H), 6.85 (d,
J = 8.4 Hz, 2H), 5.06 (m, 1H), 4.39 (s, 2H), 3.77 (s, 3H), 3.45 (t,
J = 6.6 Hz, 2H), 2.01 (s, 3H), 1.9–1.81 (m, 2H), 1.21 (d, J = 6.0 Hz,
3H). dC: 170.55, 159.20, 130.81, 129.27, 113.78, 72.65, 68.55,
½
a 2D9
ꢂ
¼ ꢀ18:5 (c 1.0, MeOH). HRMS (+ESI) calcd for C20H34O3SiNa
(M+Na+): 373.2169; found, 373.2176.
4.8. (S)-4-(4-Methoxy-benzyloxy)-hex-5-en-1-ol 7
Compound 6 (1.5 g, 4.3 mmol) was dissolved in 25 mL of MeOH.
Pyridinium para-toluene sulfonate (PPTS, 0.9 g, 4.3 mmol) was
added to the reaction mixture and it was stirred at room tempera-
ture for 6 h. After completion of the reaction, the MeOH was evap-
orated and the crude reaction mixture was taken in DCM, washed
with water, NaHO3 solution and brine. The organic layer was dried
(MgSO4) and evaporated. The crude alcohol was purified by silica
gel chromatography (3:1, hexane/EtOAc) to afford the compound
7 in 88% yield. dH: 7.25 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H),
5.75 (m, 1H), 5.24–5.19 (m, 2H), 4.52 (d, J = 11.2 Hz, 1H), 4.27 (d,
J = 11.2 Hz, 1H), 3.77 (s, 3H), 3.75 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H),
1.7–1.59 (m, 4H). dC: 159.19, 138.80, 130.48, 129.46, 117.19,
66.25, 55.23, 36.06, 21.27, 20.22. ½a D29
¼ ꢀ6:45 (c 3.0, MeOH).
ꢂ
4.12. (R)-4-(4-Methoxy-benzyloxy)-butan-2-ol 11
The acetate group was deprotected as described earlier in Sec-
113.83, 80.10, 69.88, 62.76, 55.27, 32.27, 28.78. ½a D29
ꢂ
¼ ꢀ20:2 (c
tion 4.6. ½a 2D9
¼ ꢀ24:4 (c 0.5, MeOH).
ꢂ

N. Jana et al. / Tetrahedron: Asymmetry 20 (2009) 2622–2628
2627
4.13. tert-Butyl-[(R)-3-(4-methoxy-benzyloxy)-1-methyl-
propoxy]-diphenyl-silane 12
4.17. (3R,5R)-5-(tert-Butyl-diphenyl-silanyloxy)-hex-1-en-3-ol
16
Compound 11 (6.5 g, 27.5 mmol) was taken in 100 mL of anhy-
drous DCM. Imdidazole (3.75 g, 55 mmol) was added to it at room
temperature. The reaction mixture was stirred for 15 min, after
which time TBDPS-Cl (8 mL, 33 mmol) was added to it and the
reaction mixture was stirred overnight. After completion of the
reaction, water was added to the reaction mixture and the organic
layer was washed with excess water and brine. The organic layer
was dried (MgSO4) and evaporated to dryness to afford the crude
silylated compound 12, which was purified by silica gel chroma-
tography (15:1, hexane/EtOAc). dH: 7.7 (m, 4H), 7.5–7.4 (m, 6H),
7.22 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.32 (s, 2H), 4.06
(m, 1H), 3.80 (s, 3H), 3.51 (t, J = 6.6 Hz, 2H), 1.9–1.75 (m, 2H), 1.0
(s, 9H). dC: 159.13, 135.94, 135.62, 134.42, 134.05, 130.76,
129.53, 129.46, 127.66, 127.55, 127.45, 113.76, 72.52, 67.27,
dH: 7.74 (m, 4H), 7.41 (m, 6H), 5.84 (m, 1H), 5.24 (td, J = 16.0,
2.4 Hz, 1H), 5.07 (td, J = 10.4 Hz, 2.4 Hz, 1H), 4.35 (m, 1H), 4.14
(m, 1H), 1.7–1.5 (m, 2H), 1.0 (s, 9H), 0.9 (d, J = 6.0 Hz, 3H). dC:
141.01, 135.95, 135.48, 134.51, 133.76, 129.85, 129.69, 127.79,
127.58, 114.23.
4.18. (2R,4S)-Hex-5-ene-2,4-diol 17
Compound 15 (80 mg, 0.2 mmol) was taken in dry THF (4 mL).
TBAF (1 M in THF, 0.307 mL) was added to it, and the reaction mix-
ture was stirred for 3 h at room temperature. After this time, THF
was evaporated, and water (20 mL) was added to it, the reaction
mixture was extracted with EtOAc (2 ꢁ 25 mL), the organic layer
was washed with dilute NaHCO3 solution, brine and dried (MgSO4).
It was purified by flash chromatography (1:1; hexane/EtOAc) to af-
ford the anti diol 17 in 85% yield. The spectral characteristic data
(1H and 13C NMR) were in perfect agreement with the literature
values.21
66.94, 55.31, 39.80, 27.08, 23.78, 19.34. ½a D29
¼ ꢀ22:1 (c 1.2,
ꢂ
MeOH).
4.14. (R)-3-(tert-Butyl-diphenyl-silanyloxy)-butan-1-ol 13
Compound 12 (24.5 g, 55 mmol) was taken in 150 mL of DCM/
H2O (19:1). DDQ (18.72 g, 82.5 mmol) was added to it in one por-
tion. The reaction mixture was stirred at room temperature for 1 h.
The reaction mixture was filtered off, and the filtrate was washed
with 5% NaHCO3 solution, water and brine. The organic layer was
dried (MgSO4) and evaporated. Purification by silica gel chroma-
tography (3:1, hexane/EtOAc) afforded the pure compound 13 in
86% yield. dH: 7.72–7.68 (m, 4H), 7.45–7.37 (m, 6H), 4.11 (m,
1H), 3.84 (m, 1H), 3.68 (m, 1H), 1.85 (m, 1H), 1.67 (m, 1H), 1.09
(d, J = 6.0 Hz, 3H), 1.06 (s, 9H). dC: 135.94, 135.88, 134.28, 133.79,
129.79, 129.69, 127.72, 127.57, 68.73, 59.98, 40.82, 27.03, 23.06,
4.19. (2R,4R)-Hex-5-ene-2,4-diol 18
The syn-diol 18 was obtained as described in Section 4.18 from
compound 16. The spectral characteristic data (1H and 13C NMR)
were in perfect agreement with the literature values.21
4.20. (4R,6S)-2,2,4-Trimethyl-6-vinyl-[1,3]dioxane 19
Anti diol 17 (40 mg, 0.34 mmol) was taken in 2 mL of dry
DCM. 2,2-dimethoxypropane (DMP, 0.43 mmol, 106 lL) was
added to it followed by the addition of a catalytic amount of
PPTS. The reaction mixture was stirred at room temperature
overnight. The product was purified by flash chromatography
(3:1, hexane/EtOAc) to afford the anti acetonide 19 in 80% yield.
dH: 5.90 (ddd, J = 16.0. 9.6, 7.6 Hz, 1H), 5.4 (td, J = 16.0, 1.6 Hz,
1H), 5.16 (td, J = 9.6, 1.6 Hz, 1H), 4.46 (m, 1H), 4.17 (m, 1H),
1.55 (m, 2H), 1.52 (s, 3H), 1.46 9s, 3H), 1.24 (d, J = 6.0 Hz, 3H).
dC: 140.67, 115.06, 100.18, 67.93, 62.53, 38.83, 25.72, 25.00,
21.79.
19.20. ½a 2D9
¼ ꢀ2:6 (c 2.0, MeOH).
ꢂ
4.15. (R)-3-(tert-Butyl-diphenyl-silanyloxy)-butyraldehyde 14
Oxalyl chloride (3.62 mL, 41 mmol) was taken in anhydrous
DCM (100 mL). Then DMSO (5.85 mL, 82.5 mmol) was added to
the solution and kept at -78 °C. After 5 min alcohol 13 (9 g,
27.5 mmol) was added to it, and the solution was stirred at the
same temperature for further 45 min. After this time Et3N
(23 mL, 165 mmol) was added slowly to the reaction mixture at
the same temperature. The reaction mixture was allowed to attain
room temperature. Water was added to the solution, and the mix-
ture was extracted with DCM. The organic extract was washed
with water, NaHCO3 solution and brine. The organic layer was
dried (MgSO4) and evaporated. Purification by silica gel chroma-
tography yielded the aldehyde 14 in 92% yield. dH: 9.76 (t,
J = 2.0 Hz, 1H), 7.67 (m, 4H), 7.46–7.38 (m, 6H), 4.35 (m, 1H),
2.51 (m, 2H), 1.190 (d, J = 6.4 Hz, 3H), 1.08 (s, 9H). dC: 201.98,
135.75, 135.68, 133.95, 133.50, 129.79, 129.66, 127.68, 127.53,
4.21. (4R,6R)-2,2,4-Trimethyl-6-vinyl-[1,3]dioxane 20
The syn-acetonide was prepared from the syn-diol 18 as de-
scribed in Section 4.21. dH: 5.78 (ddd, J = 16.0, 9.6, 7.6 Hz, 1H),
5.35 (td, J = 16.0, 1.6 Hz, 1H), 5.15 (td, J = 9.6, 1.6 Hz, 1H), 4.35
(m, 1H), 4.08 (m, 1H), 1.5 (s, 3H), 1.45 (s, 3H), 1.24 (d,
J = 6.0 Hz), dC: 138.83, 115.28, 98.59, 70.19, 64.86, 38.47, 30.29,
22.18, 19.82.
4.22. tert-Butyl-[(1R,3S)-3-(4-methoxy-benzyloxy)-1-methyl-
pent-4-enyloxy]-diphenyl-silane 21
65.61, 52.68, 26.85, 23.77, 19.11. ½a D29
ꢂ
¼ ꢀ1:6 (c 1.0, MeOH).
4.16. (3S,5R)-5-(tert-Butyl-diphenyl-silanyloxy)-hex-1-en-3-ol 15
Secondary hydroxyl group in compound 15 was protected as its
PMB ether as described in Section 4.7 to afford the compound 21 in
82% yield.
Vinylmagnesium bromide addition onto aldehyde 14 was per-
formed as described under Section 4.4 to yield two diastereomeric
alcohols 15 (less polar by TLC) and 16 in a 1:1 ratio. They were sep-
arated by silica gel chromatography. dH: 7.74 (m, 4H), 7.41 (m, 6H),
5.84 (m, 1H), 5.26 (td, J = 16.0, 2.4 Hz, 1H), 5.08 (td, J = 10.4 Hz,
2.4 Hz, 1H), 4.45 (m, 1H), 4.18 (m, 1H), 1.7–1.6 (m, 2H), 1.05 (d,
J = 6.0 Hz, 3H), 1.0 (s, 9H). dC: 141.30, 136.14, 136.10, 134.27,
133.74, 130.05, 129.80, 127.93, 127.80, 114.15, 69.81, 68.53,
45.12, 27.23, 23.05, 19.38.
dH: 7.67 (m, 4H), 7.5–7.32 (m, 6H), 7.25 (d, J = 8.4 Hz, 2H), 6.83
(d, J = 8.4 Hz, 2H), 5.61 (m, 1H), 5.25 (m, 2H), 4.37 (d, J = 11.8 Hz,
1H), 4.11 (q, J = 6.0 Hz, 1H), 4.03 (d, J = 11.8 Hz, 1H), 3.93 (m, 1H),
3.78 (s, 3H), 1.71 (t, J = 6.4 Hz, 2H), 1.06 (d, J = 6.0 Hz, 3H), 1.03
(s, 9H). dC: 159.23, 139.54, 136.13, 135.11, 135.02, 134.67,
131.14, 129.70, 129.61, 129.48, 127.71, 127.59, 116.74, 113.91,
76.59, 70.02, 67.04, 55.48, 46.42, 27.27, 24.47, 19.49. ½a D29
¼ þ1:0
ꢂ
(c 1.25, MeOH).

2628
N. Jana et al. / Tetrahedron: Asymmetry 20 (2009) 2622–2628
4.23. (2R,4S)-4-(4-Methoxy-benzyloxy)-hex-5-en-2-ol 22
tography with hexane/EtOAc (3:1) afforded the pure stagonolide-C
in 65% yield. dH: 5.58 (dd, J = 15.6 Hz, 9.2 Hz, 1H), 5.42 (dd,
J = 15.6 Hz, 9.2 Hz, 1H), 5.14 (m, 1H), 4.01 (m, 2H), 2.28 (m, 2H),
2.29 (m, 1H), 2.07–2.01 (m, 3H), 1.88 (dd, J = 13.2, 2.8 Hz, 1H),
1.77 (ddd, J = 13.2, 11.2, 2.8 Hz, 1H), 1.22 (d, J = 6.4 Hz, 3H). dC:
174.54 (qC), 135.81 (CH), 132.95 (CH), 74.42 (CH), 72.02 (CH),
67.75 (CH), 43.34 (CH2), 34.39 (CH2), 31.51 (CH2), 21.35 (CH3).
Compound 21 was desilylated using TBAF as described in Sec-
tion 4.18 to afford the alcohol 22 in 90% yield.
dH: 7.24 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.82 (m, 1H),
5.24 (m, 2H), 4.54 (d, J = 11.2 Hz, 1H), 4.29 (d, J = 11.2 Hz, 1H), 4.07
(m, 2H), 3.79 (s, 3H), 1.69 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H). dC:
159.18, 138.11, 130.17, 129.40, 117.05, 113.81, 76.65, 69.94,
½
a 2D9
ꢂ
¼ þ44:4 (c 1.0, MeOH). HRMS (+ESI) calcd for C10H16O4Na
64.59, 55.20, 43.57, 23.27. ½a D29
ꢂ
¼ ꢀ13:7 (c 1.25, MeOH). HRMS
(M+Na+): 223.0941, found: 223.0944.
(+ESI) calcd for C14H20O3Na (M+Na+): 259.1304; found, 259.1308.
Acknowledgements
4.24. (S)-4-(4-Methoxy-benzyloxy)-hex-5-enoic acid (1R,3S)-3-
(4-methoxy-benzyloxy)-1-methyl-pent-4-enyl ester 23
We are thankful to CSIR (New Delhi, India; Grant No. 01-2109/
07/EMR-II) for providing financial support. We are also thankful to
DST (New Delhi) for providing the departmental NMR facility un-
der the DST-FIST programme. Two of the authors N.J. and T.M.
are thankful to CSIR (New Delhi, India) for a research fellowship.
The carboxylic acid 8 (222 mg, 0.889 mmol) was taken in 5 mL
of anhydrous THF. Then, EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-
dihydroquinoline, 330 mg, 1.3 mmol) was added to the reaction
mixture and the solution was stirred for 30 min at room tempera-
ture. After this time alcohol 22 (140 mg, 0.59 mmol) was added to
it and the solution was stirred for further 4 h at the same temper-
ature. After completion of the reaction, the THF was evaporated
and the crude mixture was directly purified using silica gel chro-
matography (3:1, hexane/EtOAc) to afford the ester 23 in 92% yield.
dH: 7.25 (m, 4H), 6.86 (m, 4H), 5.71 (m, 2H), 5.25–5.15 (m, 4H), 5.10
(m, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.47 (J = 11.2 Hz, 1H), 4.27 (d,
J = 11.2 Hz, 1H), 4.24 (d, J = 11.2 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H),
3.73 (m, 1H), 2.33–2.2 m, 2H), 1.88–1.65 (m, 4H), 1.18 (d,
J = 6.4 Hz, 3H). dC: 172.77, 159.06, 159.02, 138.46, 138.34, 130.53,
130.32, 129.57, 129.28, 129.25, 117.55, 117.52, 117.04, 113.70,
79.14, 79.03, 69.86, 69.76, 67.64, 55.20, 55.17, 42.22, 30.49,
References
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30.34, 20.52. ½a D29
¼ ꢀ58:3 (c 1.5, MeOH).
ꢂ
HRMS (+ESI) calcd for C28H36O6Na (M+Na+): 491.2404; found,
491.2409.
7. McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem. 1986, 51, 3388.
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9. The enantioselectivity was determined by Chiral-HPLC (CHIRALPAK OJ-H, 254
nm) by deprotecting the acetate group and converting the free alcohol group to
its benzoate ester.
4.25. (S)-4-Hydroxy-hex-5-enoic acid (1R,3S)-3-hydroxy-1-
methyl-pent-4-enylester 24
The PMB-ether groups in compound 23 were removed as de-
scribed in Section 4.14 to afford the diol 24 in 85% yield. dH: 5.84
(m, 2H), 5.26–5.07 (m, 5H), 4.18 (m, 1H), 4.10 (m, 1H), 2.4–2.3
(m, 2H), 1.8–1.6 (m, 4H), 1.21 (d, J = 6.4 Hz, 3H). dC: 177.02,
140.54, 135.43, 117.47, 114.29, 80.45, 70.50, 65.24, 43.69, 28.65,
10. Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org.
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13. The enantioselectivity of this step was determined by measuring the specific
rotation value of 1,3-butanediol (obtained from 10 after successive
deprotection of acetate and PMB group) and comparing with that of
authentic sample.
28.20, 20.54. ½a D29
¼ ꢀ29:3 (c 0.5, MeOH). HRMS (+ESI) calcd for
ꢂ
C12H20O4Na (M+Na+): 251.1254; found, 251.1251.
4.26. (E)-(5S,8S,10R)-5,8-Dihydroxy-10-methyl-3,4,5,8,9,10-
hexahydro-oxecin-2-one (stagonolide-C)
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The diol 24 (40 mg, 0.175 mmol) was taken in anhydrous de-
gassed DCM (100 mL). Grubbs-second generation metathesis cata-
lyst (15 mg, 0.0175 mmol) was added to it and the solution was
refluxed for 6 h. The solution was evaporated and the content of
the flask was directly loaded on a silica gel column. Flash chroma-