Convergent and stereoselective synthesis of (-)-zeaenol

Article abstract of DOI:10.1016/j.tet.2015.06.035

Stereoselective synthesis of (-)-zeaenol has been accomplished from d-xylose as a chiral pool starting material. The key steps of this convergent synthetic strategy involves a Stille coupling, a Noyori reduction, a Julia-Kocienski olefination and a macrolactonization to obtain (-)-zeaenol. We have also explored a Sonogashira coupling along with a Trost protocol for the intramolecular hydrosilylation on the homopropargylic alcohol system as an alternative synthetic approach to this molecule.

Full text of DOI:10.1016/j.tet.2015.06.035

Accepted Manuscript
Convergent and Stereoselective Synthesis of (-)-Zeaenol
Rayala Naveen Kumar, H.M. Meshram
PII:
S0040-4020(15)00904-7
10.1016/j.tet.2015.06.035
TET 26870
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 March 2015
Revised Date: 3 June 2015
Accepted Date: 9 June 2015
Please cite this article as: Kumar RN, Meshram HM, Convergent and Stereoselective Synthesis of (-)-
Zeaenol, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.035.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Convergent and Stereoselective Synthesis of
-)-Zeaenol
Rayala Naveen Kumar and H. M. Meshram*
Leave this area blank for abstract info.
(

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Convergent and Stereoselective Synthesis of (-)-Zeaenol
Rayala Naveen Kumar and H. M. Meshram*
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India, Tel.: +91 40 27191640; Fax: +91
0 27193275
4
E-mail: hmmeshram@yahoo.com.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Stereoselective synthesis of (-)-zeaenol has been accomplished from D-xylose as a chiral pool
starting material. The key steps of this convergent synthetic strategy involves a Stille coupling, a
Noyori reduction, a Julia–Kocienski olefination and a macrolactonization to obtain (-)-zeaenol.
We have also explored a Sonogashira coupling along with a Trost protocol for the
intramolecular hydrosilylation on the homopropargylic alcohol system as an alternative synthetic
approach to this molecule.
Available online
Keywords:
Stille coupling
2
009 Elsevier Ltd. All rights reserved.
Intramolecular hydrosilylation
Julia–Kocienski olefination
Sonogashira coupling
D-xylose
1
. Introduction
β-Resorcylic acid lactones (RAL) represent new lead
compounds for drug discovery, particularly as new cancer
1
chemotherapeutic agents. Recently β-resorcylic acid lactones,
new paecilomycins A-F were isolated by Xu et al and co-workers2
from the mycelial solid culture of Paecilomyces sp. SC0924.
They exhibit various pharmacological activities 6such as
3
4
5
antitumor, antifungal, antifouling and antimalarial. (5Z)-7-
Oxozeaenol is a potent inhibitor of the NF-κB pathway and also
7
significantly enhances the chemotherapeutic efficacy. Thus the
syntheses of various RALs (Fig. 1) are of great importance. (-)-
Zeaenol, a 14-membered macrolide fused to a 3-methoxyphenol
ring was isolated from the plant pathogenic fungus Drechslera
portulacae. Sugawara et al determined the relative configuration
of (-)-zeaenol by single crystal X-ray diffraction together with the
Fig. 1 Structures of (-)-zeaenol and some of the natural products having
similar skeletal paecilomycins and aigilomycins.
1
13
8
assignments of H and C NMR spectra. 9 (-)-Zeaenol itself
exhibits antibacterial, herbicidal activity , antiviral and
The ability to acquire pharmaceutically active species in
required quantity by economic and scalable routes is an
important goal in natural product synthesis. To the best of our
knowledge, Sonogashira coupling along with hydrosilylation of
internal alkynes has not been studied on this type of moieties. We
believe that this is one of the best alternative approaches for the
construction of macrolactone core of RALs with required
stereochemistry and also with good overall yield. This work lays
a foundation for an eventual synthesis of β-resorcylic acid
lactones to produce a library of natural products. In continuation
of our research for the synthesis of new bioactive molecules,
herein we wish to report enantioselective synthesis of (-)-zeaenol.
1
antiprotozoan activity. Due to its impressive biological activity
and novel structure, several groups have disclosed total synthesis
10
of various RALs. However, out of these only three reports were
11
resulted in the synthesis of (-)-zeaenol. Very recently, Du and
co-workers have reported the synthesis of (-)-zeaenol from L-
arabinose by means of Suzuki cross-coupling and ring-closing
11b
metathesis (RCM) with an overall yield of 4.3%.
Salient features of this synthetic strategy include: The
construction of three adjacent stereogenic hydroxyl groups in

2
Tetrahedron
le MA
1
2
macrolactone core that is achieved from comm
A
er
C
ci
C
all
E
y
P
av
T
ai
E
lab
D
w
N
ith
U
85
S
%
CRyie
I
ld over two steps. This material was subjected to
P
T
D-xylose. The C10′ stereogenic centre could be easily generated
by Noyori reduction of readily available methyl acetoacetate.
Palladium-catalyzed Stille cross-coupling reaction was employed
for the stereospecific construction of C1′- C2′ double bond. We
also explored Sonogashira coupling as an alternative approach
for Stille coupling in this protocol. We utilized the Trost protocol
of an intramolecular hydrosilylation and a protodesilylation
which required the introduction of the trans-alkene moiety in the
sequence of the synthesis. By taking the advantage of classical
Julia–Kocienski olefination, we have constructed another C7′-
C8′ trans double bond of macrolactone core. The direct ring
closure of a substituted phenolic ester derivative was achieved to
form the 14-membered macrolactone.
thioacetal deprotection with HgO (red) and HgCl in acetonitrile-
2
water (5 : 1) that resulted in aldehyde, which was used in the next
step without further purification. In order to reduce the number of
synthetic steps, this aldehyde was directly treated with sulfone 7
under Julia–Kocienski olefination conditions that resulted in the
decomposition of aldehyde. Therefore an alternative strategy was
employed wherein the aldehyde derived from 14 was reduced
with NaBH in methanol to obtain the primary alcohol, following
4
conversion into benzyl ether 15 by treating with NaH and BnBr.
The resulting compound 15 was subjected to mono deprotection
of acetonide in the presence of 60% acetic acid that resulted in
diol 16 in moderate yield (64%). In order to increase yield of the
diol 16 various reagents like CuCl and triflouro acetic acid were
2
screened by varying temperatures as well as stoichiometries. Best
yields (93%) were obtained when 15 was treated with 50%
triflouro acetic acid at -10 °C for 30 min under high dilution.
Regioselective silylation of the primary alcohol of diol 16 using
TBSCl, imidazole in CH Cl at 0 °C afforded mono-silyl ether 17
2
2
in 86% yield. Subsequently, mesyl protection of secondary
alcohol resulted in the corresponding methanesulfonate, which
was directly subjected to the removal of TBS group with TBAF
and consecutively TBAF-mediated epoxidation was performed to
synthesize epoxide 12 in 88% yield over two steps (Scheme 2).
Epoxide ring-opening of 12 was carried out using lithium
acetylide and ethylenediamine complex, in DMSO afforded
terminal alkyne 18 in 84% yield. The resulting secondary
hydroxyl group in alkyne 18 was converted to MOM ether 19
using methoxymethyl chloride and DIPEA in THF with 84%
yield. In order to execute Stille coupling, trans vinyl stannane
precursor 9 was synthesized from terminal alkyne 19 by treating
with AIBN and tri-n-butyltin hydride in THF. On the other side,
the construction of another Stille coupling partner 10 was
achieved from commercially available 2,4,6-trihydroxybenzoic
Scheme 1 Retrosynthetic analysis of (-)-zeaenol.
As depicted in Scheme 1, we designed our retrosynthetic
strategy based on a convergent approach wherein (-)-zeaenol
could be obtained from Julia–Kocienski olefination of an
aldehyde derived from precursor 6 and sulfone 7. The sulfone 7
could be achieved from β-hydroxy ester 8 and precursor 6
envisioned from Stille coupling of vinyl stannane 9 and Aryl
triflate 10. The vinyl stannane 9 was envisioned to come from
epoxide 12 by successive implementation of the epoxide ring
opening with lithium acetylide and conversion of alkyne to trans
vinyl stannane by treating with AIBN and tributyltin hydride.
Aryl triflate 10 could be obtained easily through known
procedures from 2,4,6- trihydroxy benzoic acid 11. Epoxide 12
was envisaged as being accessible from commercially available
D-xylose 13.
13
acid 11 according to a literature procedure .
Scheme 3 Synthesis of Julia–Kocienski olefination partner aldehyde 21.
Due to versatility and reliable nature, the Stille cross-coupling
is widely employed for the formation of carbon–carbon bonds in
14
many natural products synthesis . Stille coupling between aryl
triflate 10 and vinyl stannane 9 by using a catalytic amount of
tetrakis(triphenylphosphine)palladium(0) and additive lithium
chloride afforded coupling product 6 in 82 % yield (Scheme 3).
For debenzylation, the product 6 was subjected to Lithium
naphthalenide that resulted in the decomposition of the starting
material. Exposure of 6 to a variety of benzyl deprotecting
reagents such as Lithium naphthalenide, TMSI, FeCl and BCl
3
3
failed to generate the required alcohol 20. After screening with
several reagents and reaction conditions for debenzylation,
finally we optimised the reaction conditions by treating the
olefin 6 with 1 equivalent of DDQ in DCM- phosphate buffer
Scheme 2 Synthesis of Stille coupling partner 9.
(
9:1) at 40 °C for 4 h afforded the deprotected alcohol 20 in 71%
2
. Results and discussion
15
yield . This alcohol 20 was oxidized to aldehyde by using IBX
in ethyl acetate at 85 °C reflux for 3h, which was utilised for
Julia–Kocienski olefination without further purification.
Our initial focus relied upon the construction of trans vinyl
stannane derivative 9 for which the synthesis was started from D-
xylose. Synthesis of Stille coupling partner 9 was achieved in 10
steps from 14. Accordingly, the ketal and thioacetal protected D-
xylose 14 was synthesized from the known literature procedure

3
9
1
ACCEPTED MAca
N
tal
U
ys
S
t b
C
ea
RI
PTthe chiral diphosphine ligand (S)-(-)-BINAP .
rin
g
The secondary alcohol 8 was converted to TBDPS ether and was
subjected to 2 equivalents of DIBAL resulted in the reduction of
ester to primary alcohol 25 in 79% yield over two steps as shown
in Scheme 6. Alcohol 25 was converted to the corresponding
sulfide 26 under Mitsunobu conditions in 90% yield and which
upon oxidation with m-CPBA afforded the required sulfone 7 in
8
5% yield.
Scheme 4 Sonogashira coupling followed by intramolecular
hydrosilylation and a protodesilylation.
16
We also employed a Sonogashira coupling followed by an
intramolecular hydrosilylation and a protodesilylation as an
alternative approach to Stille coupling for this molecule.
Accordingly, Sonogashira coupling was achieved from alkyne 18
and aryl triflate 10 by treating catalytic amounts of Cl Pd(PPh )
Scheme 7 Total synthesis of (-)-zeaenol.
Finally to complete the synthesis of (-)-zeaenol, we focused
20
on the Julia–Kocienski olefination of the two fragments sulfone
and aldehyde 21. Here we have optimised the reaction
2
3 2
7
(5 mol%) and CuI (10 mol%) affored 22 in 88% yield. The
condition and E: Z ratio of the coupled olefin 27 using different
bases like NaHMDS, LiHMDS and KHMDS. Accordingly,
sulfone 7 was treated with 1.5 equivalents of KHMDS and
aldehyde 21 was introduced at −78 °C to afford the coupled
product 27 (12:1= E: Z) (Scheme 7) in 86% yield (based on the
recovery of aldehyde). The E: Z ratio of the coupled olefin was
homopropargylic alcohol 22 was silylated in neat
tetramethyldisilazane (TMDS) at 60 °C (decomposition was
observed at elevated temperatures, above 80 °C) and volatile
residual TMDS was removed under reduced pressure. The
residue was then taken up in dichloromethane and treated with a
catalytic amount of ruthenium complex [Cp*Ru(MeCN) ]PF
3
6
1
17
confirmed based on coupling constant 15.7 Hz in H NMR.
(
Scheme 4) . Then the homopropargylic system underwent
Removal of the TBDPS group with TBAF on prolonged reaction
time afforded secondary alcohol 28 in 82% yield. The product 28
was subjected to a direct macrolactonization with NaH that
resulted in a tandem sequence of removal of aromatic acetonide
and formation of desired 14-membered macrolactone 29 in good
yield (85%). Global deprotection of the MOM and acetonide of
macrolide 29 in one pot was successfully achieved using 2N HCl
to generate (-)-zeaenol 1 in 94% yield. In this Stille coupling
strategy, we have successfully synthesized (-)-zeaenol 1 in 17
hydrosilylation to afford cyclic siloxane product 23. A catalytic
amount of copper(I) iodide (0.1 equiv) in the presence of TBAF
in THF effected clean protodesilylation of 23 to give trans
homoallylic alcohol 24 in 76% yield . The resultant homoallylic
alcohol was protected as it's MOM ether using methoxymethyl
chloride and DIPEA in THF with 79% yield.
18
1
13
steps from 14. H, C NMR spectral data and optical rotation
27
20
{
[α]D = -87 (c 0.5, MeOH); lit.: [α]D = -92 (c 0.52, MeOH)} of
synthetic product, (-)-zeaenol 1 was in complete agreement with
8
the natural product data .
Scheme 5 A plausible mechanism for cis silylmetalation followed by
isomerization.
3. Conclusion
1
7
The significance of our synthetic sequence lies in employing
natural chiral D-xylose to build three adjacent stereogenic centers
on the macrocyclic skeleton. Cost-effective and readily available
precursors like D-xylose and methyl acetoacetate were used as
the starting material for the synthesis. The overall yield of the
synthetic pathway in a Stille coupling strategy was 10.3% and in
a Sonogashira coupling strategy was 10.4% starting from D-
xylose, a significant enhancement over earlier synthesis which is
about 4.3%. The key synthetic reactions include a Stille coupling,
a Sonogashira coupling and intramolecular hydrosilylation as an
alternative approach, a Julia–Kocienski olefination and a direct
macrolactonization. The spectral properties and optical rotation
of the synthetic compound were found to be identical with those
published for the natural (-)-zeaenol. This synthetic protocol may
find application in drug discovery for synthesis of variety of β-
resorcylic acid lactones derivatives with wide range of biological
activity.
As Trost proposed, the mechanism of trans hydrosilylation
reactions was postulated as initial syn silylmetalation followed by
a series of rearrangements and a final reductive elimination
(
Scheme 5). The ruthinium complex effected an intramolecular
hydrosilylation producing regioselective 6-endo-dig cyclization
under very mild conditions with excellent selectivity.
Scheme 6 Synthesis of sulfone fragment 7.
The sulfone fragment
7
was synthesized from the
commercially available methyl acetoacetate over five steps. β-
hydroxy ester 8 was achieved in quantitative yield (99% ee) by
implementation of Noyori asymmetric hydrogenation on
commercially available methyl acetoacetate using ruthenium

4
Tetrahedron
4
. Experimental Section
pure 15 (3.79 g, 91 %). R = 0.6 (petroleum ether–EtOAc, 9:1);
ACCEPTED MANUSCRIPT
f
2
7
[
α] = -7.5 (c = 1.0, CHCl ). IR (KBr) ν = 2987, 2934, 2892,
D 3 max
All reactions were performed under inert atmosphere. All
1
454, 1374, 1252, 1216, 1158, 1087, 1063, 864, 739, 699,511
-1 1
glassware apparatus used for reactions are perfectly oven/flame
dried. Anhydrous solvents were distilled prior to use: THF from
Na and benzophenone; CH Cl , DMSO from CaH ; MeOH from
Mg cake. Commercial reagents were used without purification.
Column chromatography was carried out by using silica gel (60–
cm . H NMR (300 MHz, CDCl ): 7.37-7.27 (m, 5H), 4.58 (d, J
3
=
1.9 Hz, 2H), 4.16 (dt, J = 12.1, 6.8 Hz, 1H), 4.11 (dd, J = 7.9,
.9 Hz, 1H), 3.99 (dd, J = 7.9, 6.8 Hz, 1H), 3.91 (dd, J = 7.9,4.9
Hz, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.59 (d, J = 6.8 Hz, 2H), 1.44
2
2
2
4
13
(s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H). C NMR (75
1
20 mesh) unless otherwise mentioned. Analytical thin layer
MHz, CDCl ): 137.8, 128.6, 128.4, 127.9, 127.8, 109.8, 109.7,
3
chromatography (TLC) was run on silica gel 60 F254 pre-coated
plates (250 ꢀm thickness). Optical rotations [α] were measured
on a polarimeter and given in 10 degcm g . Infrared spectra
were recorded in CHCl /KBr (as mentioned) and reported in
7
8.5, 76.5, 75.7, 73.6, 70.5, 65.7, 27.1, 27.0, 26.2, 25.5; MS
+
D
(ESI): m/z = 345 [M + Na] . HRMS: calcd. for C H O Na [M +
18 26 5
+
-
1
2
−1
Na] : 345.1673: found: 345.1666.
3
−1
wave number (cm ). Mass spectral data were obtained using MS
EI) ESI, HRMS mass spectrometers. High resolution mass
(R)-1-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethane-1,2-diol (16):
(
spectra (HRMS) [ESI+] were obtained using either a TOF or a
To a flask containing protected alcohol 15 (3.22 g, 10 mmol)
in 100 mL DCM at -10 °C (ice-salt bath) was added 10 mL of
cold TFA (50%). The reaction mixture was stirred for 30 min at -
1
double focusing spectrometer. H NMR spectra were recorded at
13
3
00, 400, 500 and C NMR spectra 75, 100, 125 MHz in CDCl3
solution unless otherwise mentioned, chemical shifts are 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
1
0 °C and then add sat. NaHCO solution, stirred for 30 min at rt,
3
The layers were separated and the aqueous layer was extracted
with DCM (2x50mL), washed in turn with brine, dried over
anhydrous MgSO , concentrated under reduced pressure and
4
=
quartet, quin = quintet, sex = sextet, m = multiplet, br = broad,
purified by column chromatography (petroleum ether–EtOAc,
ABq = AB Quartet.
2
:3) gave the diol 16 (2.63 g, 93 %) as a colorless oil. R = 0.3
f
27
(petroleum ether–EtOAc, 2:3); [α]D = -15.3 (c = 1.0, CHCl ). IR
(4R,4'R,5S)-5-((benzyloxy)methyl)-2,2,2',2'-tetramethyl-
3
4
,4'-bi(1,3-dioxolane) (15):
(KBr) νmax = 3423, 3064, 2987, 2932, 1454, 1375, 1250, 1215,
-1 1
1
166, 1088, 868, 740, 700, 605, 511 cm . H NMR (300 MHz,
red HgO (5.4 g, 25 mmol) and HgCl (5.43 g, 20 mmol) were
2
CDCl ): 7.37-7.27 (m, 5H), 4.58 (d, J = 1.9 Hz, 2H), 4.24 (dt, J =
3
added to a solution of 14 (3.36 g, 10 mmol) in MeCN/H O (10:2
2
1
3
1
3
1
3.2, 6.8 Hz, 1H), 3.91 (d, J = 8.3 Hz, 1H), 3.69-3.66 (m, 3H),
.65 (ddd, J = 10.5, 7.9, 2.6 Hz, 1H), 3.58 (dd, J = 10.5, 5.3 Hz,
v/v, 36 mL) stirred at ambient temperature. One hour later the
mixture was filtered through Celite and washed with CH Cl (50
2
2
H), 2.93-2.80 (br, 1H), 2.77-2.59 (br, 1H), 1.42 (s, 3H), 1.41 (s,
mL). The filtrate and washings were washed with aq. 20% KI
and sat. NaHCO in turn and dried over anhydrous MgSO ,
13
H). C NMR (75 MHz, CDCl ): 137.5, 128.4, 127.8, 127.7,
3
3
4
09.6, 79.8, 75.8, 73.6, 70.3, 70.2, 64.6, 27.0, 26.8; MS (ESI):
Removal of the solvent results in colorless liquid. This aldehyde
used for the next step without further purification.
+
+
m/z = 305 [M + Na] . HRMS: calcd. for C H O Na [M + Na] :
18
26
5
3
05.1359: found: 305.1351.
To the above aldehyde in dry MeOH (40 mL) was added
(
R)-1-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
NaBH (740 mg, 20 mmol) portion wise at 0 °C under a nitrogen
4
dioxolan-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethanol (17):
atmosphere. After being stirred for 3 h at room temperature,
saturated aq. NH Cl was added to the reaction mixture, MeOH
To a solution of 16 (8.46 g, 30 mmol) in DCM (30 mL),
imidazole (2.25 g, 33 mmol) and TBSCl (5 g, 33 mmol) were
added at 0 °C. The mixture was stirred at room temperature for 3
4
concentrated under reduced pressure and residue extracted with
ethyl acetate (3×50 mL). The combined organic extracts were
washed with brine (50 mL), dried over anhydrous Na SO ,
h, after which time the reaction was quenched by adding H O and
2
4
2
concentrated under reduced pressure and purified by column
chromatography (petroleum ether–EtOAc, 2:3) to afford alcohol
diluted with ethyl acetate (20 mL). The layers were separated and
the aqueous layer was extracted with ethyl acetate (3x100 mL).
(
2.12 g, 92 % for 2 steps) as yellowish oil. R = 0.4 (petroleum
The organic layers were combined, dried over Na SO , filtered,
2 4
f
27
ether–EtOAc, 2:3); [α]D = -15.7 (c = 1.0, CHCl ). IR (KBr) ν
concentrated and flash column chromatography (petroleum
ether–EtOAc, 4:1) was obtained as a yellow oil 17 (10.2 g,
3
max
=
3467, 2988, 2935, 1457, 1377, 1253, 1217, 1159, 1055, 858,
-
1
1
27
5
1
3
1
1
1
11 cm . H NMR (300 MHz, CDCl ): 4.20 (dt, J = 7.0, 4.4 Hz,
86%). R
1.0, CHCl
373, 1254, 1217, 1095, 1007, 839, 778, 740, 698, 669, 511 cm .
f
= 0.6 (petroleum ether–EtOAc, 9:1); [α]
D
= -20.3 (c =
3
H), 4.06 (d, J = 8.2 Hz, 1H), 4.05 (dd, J = 8.2, 4.4 Hz, 1H),
.98 (dd, J = 8.2, 4.4 Hz, 1H), 3.89-3.84 (m, 1H), 3.81 (dd, J =
2.1, 3.5 Hz, 1H), 3.64 (dd, J = 12.0, 4.2 Hz, 1H), 2.40 (br, 1H),
.44 (s, 9H), 1.39 (s, 3H). C NMR (75 MHz, CDCl ): 109.6,
09.4, 77.6, 76.8, 74.9, 65.4, 61.9, 27.0, 26.8, 26.0, 25.3; MS
). IR (KBr) νmax = 3474, 2986, 2931, 2859, 1465,
3
-1
1
1
H NMR (300 MHz, CDCl
Hz, 2H), 4.26 (dd, J = 8.3, 4.5 Hz, 1H), 3.99 (dd, J = 8.3, 3.0 Hz,
H), 3.74 (qt, J = 10.6, 3.0 Hz, 1H), 3.68-3.54 (m, 4H), 2.19-1.97
): 7.37-7.24 (m, 5H), 4.59 (d, J = 1.9
3
13
3
1
+
13
(ESI): m/z = 255 [M + Na] . HRMS: calcd. for C H O Na [M +
(br, 1H), 1.42 (s, 3H), 1.42 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H).
NMR (100 MHz, CDCl ): 137.9, 128.3, 127.7, 127.6, 109.4,
C
11
20
5
+
Na] : 255.1203: found: 255.1199.
3
7
5
8.0, 76.0, 73.5, 70.4, 70.3, 64.4, 27.1, 26.9, 25.8, 18.2, -3.6, -
To a stirred suspension of NaH (1.03 g, 25.86 mmol) in dry
THF (20 mL) was added a solution of above alcohol (3 g, 12.93
mmol) in dry THF (10 mL) drop wise at 0 °C under a nitrogen
atmosphere. After stirring at room temperature for 15 min, benzyl
bromide was added and the reaction mixture stirred overnight.
+
.4; MS (ESI): m/z = 419 [M + Na] . HRMS: calcd. for
+
C H O SiNa [M + Na] : 419.2224: found: 419.2212.
21
36
5
(4S,5S)-4-((benzyloxy)methyl)-2,2-dimethyl-5-((S)-oxiran-
2-yl)-1,3-dioxolane (12):
The reaction mixture was quenching with saturated aq. NH Cl at
4
To a solution of 17 (3.96 g, 10 mmol) and Et N (2.8 mL, 20
3
0
°C and extracted with ether (2×50 mL). The combined organic
mmol) in CH Cl (20 mL) was added MsCl (1.17 mL, 15 mmol)
2
2
extracts were washed with brine (30 mL), dried over anhydrous
Na SO , concentrated under reduced pressure and purified by
at 0 °C. The mixture was stirred at room temperature for 4 h. The
2
4
reaction was quenched with saturated aqueous NH Cl and was
4
column chromatography (petroleum ether–EtOAc, 4:1) to afford
extracted with ethyl acetate (3x50 mL). The organic layer was

5
washed with brine, dried over MgSO , filtered
A
an
C
d
C
co
E
nc
P
en
T
tr
E
ate
D
d. MACD
N
C
U
l )
S
:
C
13
R
8.
I
2
P
,
T
128.5, 128.0, 127.8, 109.9, 96.2, 80.4, 78.9,
4
3
The residue was dissolved in THF (5.0 mL) and then TBAF [1.0
M] solution in THF (15 mL, 15 mmol) was added to this solution
at 0 °C. After the mixture was stirred for 12 h, the reaction was
77.9, 76.2, 73.6, 71.6, 70.7, 56.1, 27.4, 27.3, 21.7; MS (ESI): m/z
+
+
= 357 [M + Na] . HRMS: calcd. for C H O Na [M + Na] :
19
26
5
357.1673: found: 357.1672.
quenched with saturated aqueous NH Cl and was extracted with
ethyl acetate (3x50 mL). The organic layer was washed with
4
(
(S,E)-4-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-4-(methoxymethoxy)but-1-en-1-
yl)tributylstannane (9):
brine, dried over MgSO , filtered, and concentrated. The residue
4
was purified by column chromatography on silica gel (petroleum
ether–EtOAc, 4:1) to give 12 (2.32 g, 88% for two steps) as a
To a solution of terminal alkyne 19 (1.66 g, 5 mmol) in
anhydrous benzene ( 30 mL) at room temperature under an argon
atmosphere was added 2,2'-azobis(2-methylpropionitrile) (AIBN)
(164 mg, 1 mmol) in one portion, followed by the drop wise
addition of tri-n-butyltin hydride (2.7 mL, 10 mmol) and the
reaction was heated to 85° C. After 4 h, the reaction was cooled
to room temperature, diluted with dichloromethane (30 mL) and
concentrated in vacuo. The resultant crude was purified via silica
gel chromatography (petroleum ether–EtOAc, 6:1) to afford vinyl
stannane 9 obtained as colorless oil. (2.78 g, 89 %, 13:1= E: Z).
27
colorless oil. R = 0.5 (petroleum ether–EtOAc, 9:1); [α]D
=
f
+
6.3 (c = 1.0, CHCl ). IR (KBr) ν = 3031, 2988, 2931, 2867,
3 max
1
454, 1375, 1251, 1215, 1167, m1084, 859, 740, 699, 605, 511
-1 1
cm . H NMR (500 MHz, CDCl ): 7.36-7.26 (m, 5H), 4.60 (d, J
3
=
1.9 Hz, 2H), 4.17 (ddd, J = 12.1, 5.7, 3.7 Hz, 1H), 3.67 (dd, J =
7
6
5
.8, 5.2 Hz, 1H), 3.63 (qd, J = 10.4,5.3 Hz, 2H), 3.08 (ddd, J =
.6, 5.3, 2.6 Hz, 1H), 2.81 (dd, J = 5.0, 4.0 Hz, 1H), 2.68 (dd, J =
.0, 2.6 Hz, 1H),1.44 (s, 3H), 1.43 (s, 3H). C NMR (100 MHz,
13
CDCl ): 137.8, 128.3, 127.7, 127.6, 110.0, 78.1, 78.0, 73.5, 70.4,
3
+
20
5
1.7, 44.9, 26.9, 26.6; MS (ESI): m/z = 287 [M + Na] . HRMS:
calcd. for C H O Na [M + Na] : 287.1254: found: 287.1248.
Rf = 0.7 (petroleum ether–EtOAc, 9:1); [α]D = + 6.4 (c = 1.0,
+
15
20
4
CHCl ). IR (KBr) ν = 2956, 2925, 2854, 1729, 1599, 1548,
3
max
1
6
457, 1376, 1271, 1253, 1122, 1098, 1073, 995, 920, 860, 738,
(
S)-1-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
-1 1
97, 667, 598, 547 cm . H NMR (300 MHz, CDCl ): 7.36-7.30
3
dioxolan-4-yl)but-3-yn-1-ol (18):
(m, 5H), 5.99-5.96 (m, 1H), 4.69-4.65 (m, 2H), 4.65-4.61 (m,
To a suspension of lithium acetylide, an ethylenediamine
complex (924 mg, 10 mmol) in DMSO (5 mL) was added 12
1.32 g, 5 mmol) in DMSO (5.0 mL) at 0 °C. The reaction
mixture was stirred for 4 h at room temperature. The reaction was
2H), 4.55 (d, J = 12.4 Hz, 1H), 4.22-4.18 (m, 1H), 3.85 (dd, J =
7.8, 5.3 Hz, 1H), 3.81-3.77 (m, 1H), 3.68 (dd, J = 10.4, 3.1 Hz,
1H), 3.54 (dd, J = 10.4, 6.7 Hz, 1H), 3.32 (s, 3H), 2.46-2.41 (m,
2H), 1.55-1.43 (m, 6H), 1.41 (s, 3H), 1.40 (s, 3H), 1.35-1.23 (m,
(
13
quenched with saturated aqueous NH Cl and the whole was
6H), 0.95-0.81 (m, 15H). C NMR (100 MHz, CDCl ): 144.4,
4
3
extracted with ethyl acetate (4x100 mL). The organic layer was
138.1, 131.7, 128.3, 127.7, 127.6, 109.3, 96.2, 78.7, 77.9, 77.1,
73.3, 71.4, 55.8, 39.9, 29.2, 29.1, 27.3, 27.1, 13.7, 9.4; MS (ESI):
washed with brine, dried over MgSO , filtered, and concentrated.
4
+
The residue was purified by silica gel column chromatography
m/z = 649 [M + Na] . HRMS: calcd. for C H O SnNa [M +
31
54
5
+
(
petroleum ether–EtOAc, 7:3) to give 18 (1.22 g, 84%) as a
Na] : 649.2891: found: 649.2886.
27
colorless oil. R = 0.4 (petroleum ether–EtOAc, 1:4); [α]D = -3.4
f
5
-((S,E)-4-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-
(
c = 1.0, CHCl ). IR (KBr) ν = 3446, 3294, 2987, 2918, 2119,
3 max
1
,3-dioxolan-4-yl)-4-(methoxymethoxy)but-1-en-1-yl)-7-
1
5
454, 1375, 1252, 1214, 1166, 1086, 1046, 858, 741, 699, 644,
-1 1
methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (6):
12 cm . H NMR (300 MHz, CDCl ): 7.39-7.24 (m, 5H), 4.60
3
(
2
1
d, J = 1.9 Hz, 2H), 4.11 (dd, J = 6.0, 5.5 Hz, 1H), 3.82-3.73 (m,
H), 3.70 (dd, J = 9.6, 4.9 Hz, 1H), 3.61 (dd, J = 9.6, 6.0 Hz,
H), 3.23-3.11 (br, 1H), 2.61 (td, J = 16.8, 2.8 Hz, 1H), 2.46
Tetrakis(triphenylphosphine)palladium(0) (116 mg 0.1 mmol)
and lithium chloride (255 mg, 6 mmol) were added to 20 mL of
dry THF. This mixture was stirred for 15 min under argon
atmosphere, then a solution of Aryl Triflate 10 (712 mg, 2 mmol)
and vinyl stannane 9 (1.27 g, 2.02 mmol) in 10 mL dry THF was
added to the reaction mixture. The resulting reaction mixture was
heated to THF reflux for 24 h. The mixture is cooled to rt and
partitioned between 20 mL of water and 25 mL of diethyl ether.
The aqueous layer was extracted diethyl ether (2x20 mL). The
combined organic layers were washed with a saturated sodium
bicarbonate solution, a brine solution, dried over sodium sulphate
and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether–EtOAc,
7:3) to yield yellow thick liquid of the coupled product 6 (889
(ddd, J = 17.0, 6.2, 2.6 Hz, 1H), 2.05 (t, J = 2.6 Hz, 1H),1.39 (s,
13
3
1
H), 1.38 (s, 3H). C NMR (75 MHz, CDCl ): 137.1, 128.4,
3
27.8, 109.3, 80.4, 80.2, 78.2, 73.6, 70.6, 70.5, 53.6, 26.8, 23.9;
+
MS (ESI): m/z = 313 [M + Na] . HRMS: calcd. for C H O Na
[
17
22
4
+
M + Na] : 313.1410: found: 313.1404.
(4S,5S)-4-((benzyloxy)methyl)-5-((S)-1-
(
(
methoxymethoxy)but-3-yn-1-yl)-2,2-dimethyl-1,3-dioxolane
19):
To a solution of 18 (2.9 g, 10 mmol) in dry CH Cl (20 mL)
2
2
were added i-Pr NEt (3.6 mL, 20 mmol) and MOMCl (1.14 mL,
1
2
2
7
5 mmol) at 0 °C. The mixture was stirred at room temperature
mg, 82%). R = 0.5 (petroleum ether–EtOAc, 7:3); [α] = +7.1
f
D
for 16 h. The reaction was quenched with saturated aqueous
(c = 1.0, CHCl ). IR (KBr) ν = 2953, 2911, 2859, 2346, 1728,
3 max
NH Cl and the whole was extracted with ethyl acetate. The
1599, 1558, 1457, 1376, 1271, 1213, 1123,1074, 1033, 961, 860,
4
-
1 1
organic layer was washed with brine, dried over MgSO , filtered,
738, 697, 633, 547, 513 cm . H NMR (300 MHz, CDCl ): 7.48
4
3
and concentrated. The residue was purified by column
chromatography (petroleum ether–EtOAc, 4:1) to give 19 (2.73
(d, J = 15.7 Hz, 1H), 7.37-7.24 (m, 5H), 6.74 (d, J = 2.4 Hz, 1H),
6.34 (d, J = 2.4 Hz, 1H), 6.21 (dt, J = 15.7, 7.3 Hz, 1H), 4.72-
4.65 (m, 2H), 4.64-4.54 (m, 2H), 4.25-4.18 (m, 1H), 3.90 (dd, J =
7.4, 5.9 Hz, 1H), 3.84 (dd, J = 7.4, 5.8 Hz, 1H), 3.83 (s, 3H), 3.70
g, 82%) as a colorless oil. R = 0.5 (petroleum ether–EtOAc, 4:1);
f
27
[
α]D = -18.9 (c = 1.0, CHCl ). IR (KBr) ν = 3289, 2987,
3 max
2
6
5
932, 2119, 1454, 1374, 1250, 1214, 1100, 1035, 918, 858, 740,
(dd, J = 10.4, 3.1 Hz, 1H), 3.58 (dd, J = 10.4, 6.4 Hz, 1H), 3.32
-
1
1
13
99, 644, 515 cm . H NMR (500 MHz, CDCl ): 7.37-7.27 (m,
(s, 3H), 2.65-2.54 (m, 2H), 1.69 (s, 6H), 1.43 (s, 6H).
C
3
H), 4.76 (d, J = 6.9 Hz, 1H), 4.65 (d, J = 12.4 Hz, 1H), 4.64 (d,
NMR (100 MHz, CDCl ): 164.7, 160.0, 158.7, 143.8, 138.1,
3
J = 6.9 Hz, 1H), 4.56 (d, J = 12.4 Hz, 1H), 4.21 (dt, J = 7.0, 3.1
Hz, 1H), 3.96 (t, J = 7.0 Hz, 1H), 3.78 (dd, J = 11.6, 5.0 Hz, 1H),
130.9, 130.2, 128.3, 127.7, 127.5, 109.5, 108.4, 104.9, 103.7,
100.1, 96.2, 78.6, 78.3, 77.6, 73.4, 71.4, 55.8, 55.5, 35.0, 27.1,
+
3
3
2
.71 (dd, J = 10.2, 3.1 Hz, 1H), 3.58 (dd, J = 10.4, 6.7 Hz, 1H),
.34 (s, 3H), 2.59 (qdd, J = 17.2, 5.0, 2.8 Hz, 2H), 2.00 (dd, J =
.8 Hz, 1H), 1.43 (s, 3H), 1.40 (s, 3H). C NMR (75 MHz,
25.7, 25.5; MS (ESI): m/z = 565 [M + Na] . HRMS: calcd. for
+
C H O Na [M + Na] : 565.2414: found: 565.2395.
30
38
9
13

6
Tetrahedron
5
-((S,E)-4-((4S,5S)-5-(hydroxymethyl)-
A
2,2
C
-d
C
im
E
e
P
th
T
yl
E
-1
D
,3- MApl
NU
ace
d
S
un
C
de
R
r
I
vacuum for 45 min to remove the excess silazane.
P
T
dioxolan-4-yl)-4-(methoxymethoxy)but-1-en-1-yl)-7-methoxy-
An Argon atmosphere was then re-introduced and the residue
taken up in DCM (2.0 mL). The flask was cooled to 0 °C and
solid [Cp*Ru(MeCN) ]PF (2.5 mg, 0.005 mmol) was added to
2
,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (20):
3
6
To a solution of 6 (542 mg, 1 mmol) in 9:1 DCM: pH 7.0
the solution. The flask was allowed to warm to rt, and after 2 h,
the solution was diluted with ether (10 mL) and filtered through a
short plug of florisil, washing with additional ether (3x10 mL).
The volatile components were then removed under reduced
pressure and the resulting residue purified on a florisil column
phosphate buffer (10mL) was added 2,3-Dichloro-5,6-dicyano-
,4-benzoquinone (DDQ) (227mg, 1 mmol). The reaction
1
mixture was heated to 40 °C for 4 h. The reaction mixture was
stirred until TLC analysis indicated the completion of the
reaction. After completion of reaction, cool the reaction mixture
(petroleum ether: ether, 10:1) to afford (229 mg, 83%) the
to rt then add solid NaHCO and stir for 30 min. The organic
3
desired hydrosilyl product 23 as a colorless oil. R = 0.6
f
layers was filtered, washed with saturated sodium bicarbonate
solution, a brine solution, dried over sodium sulphate and
concentrated under reduced pressure. The residue was purified by
column chromatography (petroleum ether–EtOAc, 2:3) to yield
thick liquid of the alcohol 20 (321 mg, 71%). R = 0.3 (petroleum
ether–EtOAc, 1:1); [α]D = -6 (c = 1.0, CHCl ). IR (KBr) ν
27
(petroleum ether–EtOAc, 9:1); [α]D = -57.5 (c = 1.0, CHCl ). IR
3
(
KBr) νmax =2931, 2858, 1728, 1684, 1604, 1577, 1504, 1455,
-1
1
1
347, 1245, 1111, 1032, 918, 839, 778, 737, 696 cm . H NMR
(300 MHz, CDCl ): 7.42-7.26 (m, 5H), 6.69 (dd, J = 9.1, 2.3 Hz,
3
f
27
1H), 6.47 (d, J = 2.3 Hz, 1H), 6.41-6.37 (m, 1H), 5.47-5.35 (m,
H), 4.64 (dd, J = 12.8, 5.3 Hz, 1H), 4.19 (dd, J = 12.1, 6.0 Hz,
1H), 4.08 (td, J = 7.6, 2.7 Hz, 1H), 3.89 (s, 3H), 3.68 (td, J = 7.6,
=
3
max
2
3
1
423, 2976, 2921, 2846, 1729, 1576, 1548, 1509, 1339, 1213,
149, 1122, 994, 960, 859, 621, 545, 488 cm . H NMR (300
-1 1
2
1
1
1
7
.3 Hz, 1H), 3.59-3.46 (m, 1H), 2.14-1.99 (m, 2H), 1.77 (s, 6H),
.30 (s, 6H), 0.15 (s, 6H). C NMR (75 MHz, CDCl ): 165.0,
61, 158.9, 144.2, 142.4, 138.3, 131.4, 128.6, 128.0, 127.9,
27.9, 127.8, 127.7, 111.9, 110.5, 109.5, 105.7, 100.6, 80.7, 79.9,
3.6, 72.4, 71.6, 55.9, 35.4, 29.9, 27.4, 26.0, 25.9, 25.6, 0.6, 0.5;
MHz, CDCl ): 7.47 (d, J = 15.7 Hz, 1H), 6.74 (d, J = 2.4 Hz,
13
3
3
1
H), 6.35 (d, J = 2.4 Hz, 1H), 6.20 (d, J = 15.4, 7.2 Hz, 1H), 4.75
ABq, J = 6.7 Hz, 2H), 4.17-4.09 (m, 1H), 3.98 (dd, J = 7.5, 6.4
Hz, 1H), 3.87 (dd, J = 9.6, 5.5 Hz, 1H), 3.85 (s, 3H), 3.84 (dd, J
5.7, 4.0 Hz, 1H), 3.74 (dd, J = 11.7, 4.7 Hz, 1H), 3.40 (s, 3H),
.71-2.58 (m, 2H), 2.37-2.23 (br, 1H), 1.71 (s, 3H), 1.70 (s, 3H),
(
=
+
MS (ESI): m/z = 555 [M + H] . HRMS: calcd. for C H O Si [M
30
39
8
2
1
1
7
+
13
+ H] : 555.2414: found: 555.2408.
.42 (s, 6H). C NMR (75 MHz, CDCl ): 164.8, 160.2, 158.7,
43.7, 131.2, 129.8, 109.2, 108.5, 105.0, 103.6, 100.2, 96.2, 79.3,
8.2, 77.5, 63.4, 56.0, 55.6, 35.0, 29.7, 27.1, 27.0, 25.7, 25.4; MS
3
5-((S,E)-4-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)-4-hydroxybut-1-en-1-yl)-7-methoxy-2,2-
dimethyl-4H-benzo[d][1,3]dioxin-4-one (24):
+
(ESI): m/z = 475 [M + Na] . HRMS: calcd. for C H O Na [M +
23
32
9
+
Na] : 475.1944: found: 475.1946.
The above hydrosilyl product 23 (222 mg, 0.4 mmol) was
taken up in THF (3.4 mL) under Argon at rt. To the solution was
added CuI (8 mg, 0.04 mmol) followed by dropwise addition of
TBAF [1.0 M] solution in THF (1 mL, 1 mmol) and the resulting
orange slurry was stirred for 12 h at rt. The reaction was
5
-((S)-4-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-4-hydroxybut-1-yn-1-yl)-7-methoxy-2,2-
dimethyl-4H-benzo[d][1,3]dioxin-4-one (22):
To a solution of 18 (147 mg, 0.5 mmol) in CH CN (4 mL)
3
quenched with saturated aqueous NH Cl and was extracted with
4
were added Et N (0.14 mL, 1 mmol) and Cl Pd(PPh ) (18mg,
3
2
3 2
ethyl acetate (3x10 mL). The organic layer was washed with
brine, dried over MgSO , filtered, and concentrated. The residue
was purified by column chromatography on silica gel (petroleum
ether–EtOAc, 3:2) to give 24 (151 mg, 76%) as a thick liquid. Rf
0
.025 mmol). After the mixture had been stirred for 30 min, the
4
solution of Triflate 10 (178 mg, 0.5 mmol) and CuI (10 mg, 0.05
mmol) were added and the resulting mixture was stirred for 10 h.
The reaction was quenched with saturated aqueous NH Cl (5 mL)
and the whole was extracted with ether. The organic layer was
washed with brine, dried over MgSO , filtered and concentrated.
The residue was purified by column chromatography (petroleum
ether–EtOAc, 3:2) to give 22 (217 mg, 88%) as a yellow thick
liquid. R = 0.4 (petroleum ether–EtOAc, 4:1); [α] = -74.3 (c =
4
20
=
0.3 (petroleum ether–EtOAc, 4:1); [α]D = -13.1 (c = 1.0,
CHCl ). IR (KBr) ν = 3447, 2989, 2929, 1734, 1606, 1575,
3
max
4
-
1
.
457, 1311, 1281, 1208, 1159, 1034, 971, 915, 802, 700, 641 cm
H NMR (300 MHz, CDCl ): 7.41 (d, J = 15.9 Hz, 1H), 7.36-
3
1
1
27
7.23 (m, 5H), 6.72 (d, J = 2.7 Hz, 1H), 6.35 (d, J = 2.7 Hz, 1H),
.19 (td, J = 15.9, 7.6 Hz, 1H), 4.60 (d, J = 2.3 Hz, 2H), 4.14 (td,
f
D
6
1
1
6
5
.0, CHCl ). IR (KBr) ν = 3458, 2988, 2932, 2236, 1740,
602, 1575, 1457, 1373, 1277, 1206, 1165, 1032, 914, 857, 741,
99, 673, 510 cm . H NMR (300 MHz, CDCl ): 7.37-7.22 (m,
H), 6.72 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 4.63 (d, J
3 max
J = 15.1, 7.6 Hz, 1H), 3.84 (s, 3H), 3.82-3.73 (m, 1H), 3.70-3.66
(m, 2H), 2.65 (ddd, J = 14.4, 6.8, 1.5 Hz, 1H), 2.40 (td, J = 7.6,
-
1
1
3
13
6
.8 Hz, 1H), 1.70 (s, 6H), 1.41 (s, 6H). C NMR (75 MHz,
CDCl ): 164.9, 160.3, 158.6, 144.0, 137.6, 131.8, 130.1, 128.4,
3
=
12.1 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.33-4.27 (m, 2H),
1
27.8, 127.7, 109.2, 108.6, 105.1, 103.7, 100.3, 80.9, 78.5, 73.6,
3
1
1
3
1
9
2
.91-3.86 (br, 1H), 3.87-3.84 (m, 2H), 3.82 (s, 3H), 3.66 (dd, J =
0.4, 6.4 Hz, 1H), 2.90 (dd, J = 17.2, 3.2 Hz, 1H), 2.72 (dd, J =
7.2, 6.4 Hz, 1H), 1.68 (s, 3H), 1.67 (s, 3H), 1.43 (s, 3H), 1.39 (s,
H). C NMR (75 MHz, CDCl ): 164.8, 159.6, 158.3, 138.1,
28.1, 127.5, 127.3, 126.7, 114.6, 109.5, 106.6, 105.6, 101.7,
3.8, 81.5, 79.9, 78.6, 73.3, 72.1, 71.3, 55.7, 27.0, 26.9, 26.4,
7
2.0, 70.9, 55.6, 37.2, 27.0, 26.9, 25.7, 25.5; MS (ESI): m/z =
+
+
5
21 [M + Na] . HRMS: calcd. for C H O Na [M + Na] :
28 34 8
13
521.2151: found: 521.2140.
3
5-((S,E)-4-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)-4-(methoxymethoxy)but-1-en-1-yl)-7-
methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (6):
+
5.6, 25.3; MS (ESI): m/z = 519 [M + Na] .
5
-((S)-6-((4R,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
To a solution of 24 (498 mg, 1 mmol) in DCM (5.0 mL) were
dioxolan-4-yl)-2,2-dimethyl-5,6-dihydro-2H-1,2-oxasilin-3-
yl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one
added i-Pr NEt (0.36 mL, 2 mmol) and MOMCl (0.12 mL, 1.5
mmol) at 0 °C. The mixture was stirred at room temperature for
2
(23):
12 h. The reaction was quenched with saturated aqueous NH Cl
4
and the whole was extracted with ethyl acetate. The organic layer
A rb flask was charged with 22 (248 mg, 0.50 mmol) under
was washed with brine, dried over MgSO , filtered, and
4
Argon atmosphere at rt. To the neat alcohol was added 1,1,3,3-
tetramethyldisilazane (TMDS) (270 ꢀL, 1.5 mmol) and the flask
heated to 60 °C for 5 h. Next, the flask was cooled to rt and
concentrated. The residue was purified by column
chromatography (petroleum ether–EtOAc, 3:2) to give 6 (428
mg, 79%) as a yellowish thick liquid. For data see above

7
(
S)-methyl 3-hydroxybutanoate (8):
ACCEPTED MAN(S
U
)-
S
5-
C
((3
R
-((
I
tert-butyldiphenylsilyl)oxy)butyl)thio)-1-
P
T
phenyl-1H-tetrazole (26):
Preparations of the β-hydroxy ester 8 were carried out as
20
described by Noyori and co-workers who have described the
asymmetric reduction of methyl acetoacetate using a ruthenium
catalyst bearing the chiral diphosphine ligand (S)-(-)-BINAP
enantiomers commercially available from Aldrich Chemicals. β-
hydroxy ester reduction was conducted on a 30 g scale in
Hasteloy steel autoclave vessels using a MeOH (30 mL) solvent.
Add Diisopropyl azodicarboxylate (2.6 mL, 13 mmol) to the
stirred solution of alcohol 25 (3.28 g, 10 mmol) and PPh (3.15 g,
12 mmol) in THF (30 mL) at –20 °C. Then add PTSH (1-phenyl-
5-mercapto-1H-tetrazole) (2.31 g, 13 mmol) in THF (30 mL) to
the reaction mixture and stir the reaction mixture for 30 min at 0
°C, poured into water and extracted with ethyl acetate(3x30 mL).
3
The reactions were allowed to proceed at constant H pressure
The organic layer was washed with saturated NaHCO solution
2
3
(1500 psi) for 36 h at 25 °C. Complete conversion of the methyl
and brine, dried with anhydrous MgSO and the solvent was
4
acetoacetate was observed and the products were simply distilled
from the crude reaction mixture. Consistent with the results of
Noyori et al, β-hydroxy ester 8 was determined to be 99%
removed under reduced pressure. The residue was purified by
flash column chromatography on silica gel (petroleum ether–
EtOAc, 6:1) to obtain sulfide 26 (4.4 g, 90%) as a white solid. R
f
27
enantiomerically pure. R = 0.2 (petroleum ether–EtOAc, 9:1);
= 0.5 (petroleum ether–EtOAc, 9:1); [α]D = +3.4 (c = 1.0,
CHCl ). IR (KBr) ν = 2958, 2929, 1494, 1464, 1355, 1108,
f
20
[
1
α]D = +19.6 (c = 1.0, CHCl ). IR (KBr) ν = 3424, 1735,
440, 1379, 1296, 1175, 1087, 1007, 945, 848, 602 cm . H
3
max
3
max
-
1
1
-1
1
1075, 1018, 977, 823, 764, 702, 612, 509 cm . H NMR (300
NMR (300 MHz, CDCl ): 4.27-4.15 (m, 1H), 3.72 (s, 3H), 3.01-
MHz, CDCl ): 7.73-7.26 (m, 4H), 7.59-7.49 (m, 5H), 7.45-7.29
3
3
2
3
.89 (br, 1H), 2.47 (dd, J = 8.3, 6.8 Hz, 2H) 1.23 (d, J = 6.8 Hz,
(m, 6H), 4.00 (sex, J = 6.0 Hz, 1H), 3.52-3.33 (m, 2H), 1.97 (td,
13
13
H). C NMR (75 MHz, CDCl ): 172.8, 63.9, 51.3, 42.6, 22.3;
J = 7.6, 6.3 Hz, 2H), 1.12 (d, J = 6.3 Hz, 3H), 1.05 (s, 9H).
C
3
+
MS (EI): m/z = 141 [M + Na] .
NMR (75 MHz, CDCl ): 135.8, 135.8, 129.7, 129.9, 129.6,
3
1
27.6, 129.5, 127.6, 68.0, 38.3, 29.4, 26.9, 23.1, 19.2; MS (ESI):
+
(
S)-3-((tert-butyldiphenylsilyl)oxy)butan-1-ol (25):
m/z = 511 [M + Na] . HRMS: calcd. for C H N OSSiNa [M +
Na] : 511.1958: found: 511.1939.
27
32
4
+
To a solution of 8 (2.36 g, 20 mmol) in DCM (20 mL),
imidazole (1.64 g, 24 mmol) and TBDPSCl (6.55 g, 24 mmol)
were added at 0 °C. Then the mixture was allowed to room
temperature and stirred for 3 h, after which time the reaction was
(S)-5-((3-((tert-butyldiphenylsilyl)oxy)butyl)sulfonyl)-1-
phenyl-1H-tetrazole (7):
quenched by adding H O and diluted with ethyl acetate (50 mL).
To a solution of the above sulfide 26 (976 mg, 2 mmol) in
CH Cl (10 mL) at 0 °C was added m-CPBA (1.03 g, 6 mmol).
2
The layers were separated and the aqueous layer was extracted
with ethyl acetate (3x100 mL). The organic layers were
combined, dried over Na SO , filtered, concentrated and flash
2
2
The reaction mixture was stirred at room temperature for 3 h and
the reaction mixture was poured into Na S O solution (10 %)
2
4
2
2
3
column chromatography gel (petroleum ether–EtOAc, 6:1) to
obtained (S)-methyl 3-((tert-butyldiphenylsilyl)oxy)butanoate as
and extracted with ethyl acetate (3x50 mL). The organic layer
was washed with saturated NaHCO solution and the organic
3
20
yellow oil. R = 0.8 (petroleum ether–EtOAc, 9:1); [α] = +4.1
layers were combined, dried over Na SO , filtered, concentrated
f
D
2
4
(
1
c = 1.0, CHCl ). IR (KBr) ν = 3071, 2959, 2932, 2858, 1740,
430, 1378, 1298, 1194, 1083, 998, 822 739, 705, 611, 509 cm .
and flash column chromatography (petroleum ether–EtOAc, 6:1)
3
max
-
1
was obtained sulfone 7 (884 mg, 85%) as pale yellow thick
1
27
D
H NMR (300 MHz, CDCl ): 7.72 (t, J = 7.1 Hz, 4H), 7.47-7.37
liquid. R = 0.6 (petroleum ether–EtOAc, 9:1); [α] = -2.2 (c =
3
f
(
m, 6H), 4.39-4.32 (m, 1H), 3.61 (s, 3H), 2.60 (dd, J = 14.1, 7.1
1.0, CHCl ). IR (KBr) ν = 3071, 2960, 2931, 2857, 1497,
3 max
-1 1
Hz, 1H), 2.43 (dd, J = 14.1, 6.0 Hz, 1H), 1.15 (d, J = 6.0 Hz, 3H),
1
1
m/z = 379 [M + Na] . HRMS: calcd. for C H O SiNa [M +
Na] : 379.1699: found: 379.1697.
1427, 1343, 1151, 1108, 1074, 1017, 822, 763, 616, 507 cm . H
13
.07 (s, 9H). C NMR (75 MHz, CDCl ): 171.7, 135.7, 134.1,
NMR (300 MHz, CDCl ): 7.73-7.64 (m, 5H), 7.63-7.52 (m, 4H),
3
3
33.7, 129.5, 127.4, 66.8, 51.2, 44.3, 26.8, 23.5, 19.0; MS (ESI):
7.48-7.33 (m, 6H), 4.09-4.02 (m, 1H), 3.92-3.83 (m, 1H), 3.78-
+
3.69 (m, 1H), 2.14-1.97 (m, 2H), 1.12 (d, J = 6.3 Hz, 3H), 1.05
21
28
3
+
13
(s, 9H). C NMR (75 MHz, CDCl ): 153.3, 135.7, 134.4, 133.8,
3
1
3
33.3, 131.3, 129.8, 129.7, 129.6, 127.7, 127.5, 125.0, 67.2, 52.5,
Diisobutylaluminium hydride (DIBAL) in hexane 2.0 M (20
mL, 40 mmol) was added dropwise under a nitrogen atmosphere
at 0° C to the stirred solution of above TBDPS protected ester in
dichloromethane (80 mL). Then the solution was stirred for 2
hours at room temperature. Following this, saturated ammonium
chloride solution was added to the reaction mixture and dilution
with diethyl ether (100 mL). The reaction solution was filtered
through a Celite filter. The filtrate was dried over magnesium
sulfate and the solvent was removed under reduced pressure. The
residue was then separated using silica-gel column
chromatography (petroleum ether–EtOAc, 1:1) to obtain alcohol
+
1.0, 26.9, 22.8, 19.1; MS (ESI): m/z = 543 [M + Na] . HRMS:
+
calcd. for C H N O SSiNa [M + Na] : 543.1857: found:
5
27
32
4
3
43.1842.
5-((S,E)-4-((4S,5S)-5-((S,E)-4-((tert-
butyldiphenylsilyl)oxy)pent-1-en-1-yl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-4-(methoxymethoxy)but-1-en-1-yl)-7-methoxy-
2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (27):
To the stirred solution of alcohol 20 (180 mg, 0.40 mmol) in
ethyl acetate (5 mL) was added IBX (370 mg, 0.6 mmol) at rt,
then heat the reaction mixture at 85 °C reflux for 3 h and check
TLC for the completion of reaction. After completion of
2
5 (3.4 g, 79 %, for two steps) as a colorless liguid. R = 0.4
f
20
(petroleum ether–EtOAc, 1:1); [α]D = +4.3 (c = 1.0, CHCl ). IR
3
reaction, quench with saturated aqueous NaHCO (20 mL) and
3
(
1
KBr) νmax = 3381, 3070, 2961, 2931, 2857, 1468, 1427, 1378,
109, 1027, 821, 704, 611, 507 cm . H NMR (300 MHz,
-
1
1
the mixture stirred for 30 min. The organic layer was extracted
with ethyl acetate (3x20mL), dried over MgSO4 and rotary
evaporated to give the corresponding aldehyde 21 as a colourless
oil. Rf 0.35 (petroleum ether–EtOAc, 1:1). This aldehyde used
for further reaction without purification.
CDCl ): 7.79-7.65 (m,4H), 7.51-7.33 (m, 6H), 4.12 (sex, J = 6.0
3
Hz, 1H), 3.84 (ddd, J = 8.3, 4.5, 3.0 Hz, 1H), 3.70 (q, J = 5.3 Hz,
1
H), 2.29-2.10 (br, 1H), 1.81 (ddd, J = 8.3, 5.3, 4.5 Hz, 1H), 1.65
(
9
ddd, J = 10.6, 8.3, 5.3, Hz, 1H), 1.08 (d, J = 6.0 Hz, 3H), 1.06 (s,
13
H). C NMR (75 MHz, CDCl ): 135.8, 135.7, 129.7, 129.6,
A solution of sulfone 7 (240 mg, 0.46 mmol) in THF (5 mL)
was cooled -78 °C and KHMDS 0.5M solution in toluene (1.38
mL, 0.69 mmol) was added dropwise to the reaction mixture.
After stirring for 30 minutes at -78 °C, above prepared aldehyde
3
1
+
27.5, 68.7, 59.9, 40.6, 26.9, 23.0, 19.1; MS (ESI): m/z = 351 [M
+
+
Na] . HRMS: calcd. for C H O SiNa [M + Na] : 351.1751:
20 28 2
found: 351.1744.

8
Tetrahedron
he MA
2
1 (175 mg, 0.4 mmol) in THF (5 mL) w
reaction mixture at -78 °C. The resulting mixture was stirred at -
8 °C for 3 h before saturated aqueous NH Cl (10 mL) was
A
a
C
s
C
ad
E
de
P
d
T
to
E
t
D
w
N
ith
U
b
S
rin
C
e,
R
d
I
ried over MgSO4 and concentrated. The crude
P
T
product was purified by column chromatography on silica gel
7
(petroleum ether–EtOAc, 7:3) to afford compound 29 (76 mg,
4
added. The resulting phases were separated and the aqueous layer
was extracted with EtOAc (3x25 mL). The combined organic
layers were washed with brine (10 mL), dried over MgSO4,
filtered and the solvents were evaporated under reduced pressure.
The residue was purified by flash column chromatography on
silica gel (petroleum ether–EtOAc, 7:3) to obtain trans-olefin 27
85%) as a colorless thick liquid. R = 0.4 (petroleum ether–
f
27
EtOAc, 4:1); [α]D = -80.2 (c = 1.0, CHCl ). IR (KBr) ν
=
3
max
2924, 2854, 1711, 1649, 1548, 1458, 1377, 1315, 1253, 1210,
-
1
1
1116, 1035, 967, 921, 743, 631, 508, 484 cm . H NMR (300
MHz, CDCl ): 11.54 (s, 1H), 7.17 (dd, J = 15.4, 2.0 Hz, 1H),
3
6.46 (d, J = 2.6 Hz, 1H), 6.40 (d, J = 2.6 Hz, 1H), 5.99 (ddd, J =
15.4, 8.4, 7.0 Hz, 1H), 5.72 (ddd, J = 15.4, 10.7, 3.1 Hz, 1H),
5.54 (dd, J = 15.4, 8.4, 1.2 Hz, 1H), 5.45-5.38 (m, 1H), 4.48 (d, J
= 6.7 Hz, 1H), 4.73 (d, J = 6.7 Hz, 1H), 4.63(t, J = 8.0 Hz, 1H),
4.15 (ddd, J = 12.4, 5.2, 1.8 Hz, 1H), 3.89 (dd, J = 7.8, 2.0 Hz,
1H), 3.82 (s, 3H), 3.44 (s, 3H), 2.57-2.41 (m, 2H), 2.37-2.26 (m,
(255 mg, 86% based on recovery of aldehyde, 9:1= E: Z) as a
colorless thick liquid. R = 0.3 (petroleum ether–EtOAc, 4:1);
f
27
[
α]D = - 67 (c = 1.0, CHCl ). IR (KBr) ν =2958, 2926,2856,
3 max
1
1
729, 1605, 1574, 1460, 1378, 1275, 1206, 1158, 1111, 1069,
034, 970, 916, 822, 704, 611, 512, 451 cm . H NMR (300
-1 1
1
3
MHz, CDCl ): 7.69-7.64 (m, 4H), 7.48 (d, J = 15.7 Hz, 1H),
2H), 1.44 (d, J = 6.4 Hz, 3H), 1.41 (s, 3H), 1.36 (s, 3H).
C
3
7
1
1
4
3
3
9
1
1
8
2
.43-7.33 (m, 6H), 6.74 (d, J = 2.6 Hz, 1H), 6.34 (d, J = 2.4 Hz,
H), 6.20 (dt, J = 15.7, 7.3 Hz, 1H), 5.79 (td, J = 15.0, 7.3 Hz,
H), 5.48 (dd, J = 15.0, 7.6 Hz, 1H), 4.72 (ABq, J = 6.7 Hz, 2H),
.40 (t, J = 7.9 Hz, 1H), 3.94-3.84 (m, 3H), 3.88 (s, 3H), 3.36 (s,
H), 2.60-2.44 (m, 2H), 2.33-2.17 (m, 2H), 1.70 (s, 3H), 1.69 (s,
H), 1.41 (s, 3H), 1.40 (s, 3H), 1.06 (d, J = 6.3 Hz, 1H), 1.04 (s,
NMR (75 MHz, CDCl ): 170.8, 164.7, 163.9, 142.1, 133.7,
132.4, 128.9, 127.2, 108.5, 107.1, 104.3, 100.1, 97.2, 81.6, 75.5,
3
74.2, 70.8, 55.5, 55.3, 38.0, 36.6, 27.1, 26.6, 19.5; MS (ESI): m/z
+
+
= 471 [M + Na] . HRMS: calcd. for C H O Na [M + Na] :
24
32
8
471.1995: found: 471.2019.
13
(3S,5E,7S,8S,9S,11E)-7,8,9,16-tetrahydroxy-14-methoxy-3-
methyl-3,4,7,8,9,10-hexahydro-1H-
benzo[c][1]oxacyclotetradecin-1-one (zeaenol) (1):
H). C NMR (75 MHz, CDCl ): 164.7, 160.0, 158.7, 143.7,
3
35.8, 134.5, 134.3, 132.0, 130.8, 130.7, 130.6, 130.2, 129.5,
29.4, 128.7, 127.5, 127.4, 108.6, 108.3, 104.9, 103.6, 100.1,
2.0, 78.4, 76.6, 69.0, 55.7, 55.5, 42.3, 35.1, 27.0, 26.9, 26.8,
HCl (2N, 10 mL) was added to a solution of macrolide 29 (68
mg, 0.15 mmol) in THF (10 mL) and the mixture was stirred for
+
5.7, 25.5, 22.8, 19.4; MS (ESI): m/z = 767 [M + Na] . HRMS:
+
calcd. for C H O SiNa [M + Na] : 767.3591: found: 767.3637.
24 h, quenched with saturated aqueous NaHCO solution, and
43
56
9
3
extracted with EtOAc. The organic layers were combined and
5
-((S,E)-4-((4S,5S)-5-((S,E)-4-hydroxypent-1-en-1-yl)-2,2-
dried with anhydrous MgSO , filtered, and concentrated under
4
dimethyl-1,3-dioxolan-4-yl)-4-(methoxymethoxy)but-1-en-1-
yl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one
28):
reduced vacuum. The crude product was purified by flash column
chromatography (MeOH–DCM, 1:19) to yield zeaenol 1 as a
(
white crystalline solid (51 mg, 94%). m.p. 196-199° C. R = 0.3
f
27
The compound 27 (224 mg, 0.3 mmol) was dissolved in THF
10 mL), and then TBAF [1.0 M] solution in THF (2.4 mL, 2.4
mmol)] was added to this solution at 0 °C. Stir the mixture at rt
for 24 h. the reaction was quenched with saturated aqueous
(MeOH–DCM, 1:19); [α]D = -87 (c = 0.5, MeOH). IR (KBr)
νmax = 3675, 3424, 2958, 2925, 2855, 1727, 1607, 1572, 1422,
1355, 1314, 1258, 1208, 1159, 1072, 967, 830, 740, 701, 629,
(
-
1 1
556.485. cm . H NMR (500 MHz, CDCl ): 11.89 (s, 1H), 7.10
3
NH Cl and the whole was extracted with AcOEt. The organic
(d, J = 15.4 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 6.38 (d, J = 2.6
Hz, 1H), 5.97 (td, J = 15.4, 6.1 Hz, 1H), 5.84 (ddd, J = 15.3,
10.4, 3.4 Hz, 1H), 5.69 (dd, J = 15.4, 7.5 Hz, 1H), 5.36-5.28 (m,
1H), 4.25 (t, J = 7.8 Hz, 1H), 3.95 (t, J = 6.7 Hz, 1H), 3.81 (s,
3H), 3.88-3.72 (br, 1H), 3.59 (d, J = 7.9 Hz, 1H), 2.64-2.41 (br,
2H), 2.61-2.45 (m, 2H), 2.44-2.25 (m, 2H), 1.44 (d, J = 6.3 Hz,
4
layer was washed with brine, dried over MgSO , filtered, and
4
concentrated. The residue was purified by column
chromatography on silica gel (petroleum ether–EtOAc, 2:3) to
give 28 (124 mg, 82%) as a colorless oil. R = 0.3 (petroleum
f
27
ether–EtOAc, 1:1); [α]D = +56 (c = 1.0, CHCl ). IR (KBr) ν
=
3
max
13
2
1
7
2
924, 2854, 1727, 1605, 1573, 1456, 1376, 1277, 1205, 1159,
3H). C NMR (75 MHz, CDCl +CD OD-1:1): 170.9, 164.9,
3 3
-
1 1
033, 970, 916, 743, 561, 512 cm . H NMR (300 MHz, CDCl ):
163.7, 142.7, 133.4, 131.7, 129.0, 128.7, 107.3, 104.0, 100.0,
3
.48 (d, J = 15.6 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.35 (d, J =
.4 Hz, 1H), 6.19 (dt, J = 15.6, 7.3 Hz, 1H), 5.92 (d, J = 15.4, 7.2
77.2, 72.4, 71.4, 55.4, 37.5, 35.8, 19.3, 12.4; MS (ESI): m/z =
+
+
387 [M + Na] . HRMS: calcd. for C H O Na [M + Na] :
19
24
7
Hz, 1H), 5.65 (dd, J = 15.4, 7.9 Hz, 1H), 4.75 (ABq, J = 6.7 Hz,
387.1420: found: 387.1442.
2
2
2
1
1
1
3
H), 4.48 (t, J = 8.0 Hz, 1H), 3.96-3.90 (m, 1H), 3.90-3.86 (m,
H), 3.85 (s, 3H), 3.39 (s, 3H), 2.63-2.50 (m, 2H), 2.33-2.20 (m,
H), 2.09-2.00 (br, 1H), 1.71 (s, 3H), 1.70 (s, 3H), 1.42 (s, 6H),
Acknowledgements
13
.21 (d, J = 6.3 Hz, 3H). C NMR (75 MHz, CDCl ): 164.7,
RNK thank CSIR, New Delhi for the award of fellowship and
to Dr. Ahmed Kamal, Outstanding Scientist and Head, MCP
Division, IICT, for his support and encouragement. The authors
thank CSIR, New Delhi for financial support as part of XII Five
Year plan programme under title ORIGIN (CSC-0108).
3
60.1, 158.7, 143.6, 132.2, 131.0, 130.8, 130.4, 108.6, 108.3,
04.9, 103.5, 100.2, 96.6, 81.7, 78.2, 76.2, 67.0, 55.7, 55.5, 41.9,
5.1, 27.0, 26.8, 25.6, 25.4, 22.8; MS (ESI): m/z = 529 [M +
+
+
Na] . HRMS: calcd. for C H O Na [M + Na] : 529.2414:
27
38
9
found: 529.2427.
References
(3aS,4E,7S,14E,17S,17aS)-10-hydroxy-12-methoxy-17-
(
3
methoxymethoxy)-2,2,7-trimethyl-6,7,17,17a-tetrahydro-
aH-benzo[c][1,3]dioxolo[4,5-i][1]oxacyclotetradecin-9(16H)-
one (29):
1
.
Ayers, S.; Graf, T. N.; Adcock, A. F.; Kroll, D. J.; Matthew, S.;
Carcache de Blanco, E. J.; Shen, Q.; Swanson, S. M.; Wani, M.
C.; Pearce, C. J.; Oberlies, N.H. J. Nat. Prod. 2011, 74, 1126-
1
131.
A solution of alcohol 28 ( 101 mg, 0.2 mmol) in anhydrous
2
.
Xu, L.; He, Z.; Xue, J.; Xiaoping Chen, X.; Wei, X. J. Nat. Prod.
2010, 73, 885–889
THF (5 mL) was added to a suspension of 60% NaH in mineral
oil (40 mg, 1 mmol) in THF (1 mL) at 0 °C and the mixture was
3. Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M. J. Org. Chem.
002, 67, 1561.
2
stirred for 2 h at rt, then quenched with saturated NH Cl. The
4
organic phase was extracted with EtOAc (3x20 mL), washed

9
4
5
.
.
Shier, W. T.; Shier, A. C.; Xie, W.; Mirocha, C. J. Toxicon 2001,
ACCEPTED MANUSCRIPT
3
9, 1435–1438.
Shao, C. L.; Wu, H. X.; Wang, C. Y.; Liu, Q. A.; Xu, Y.; Wei, M.
Y.; Qian, P. Y.; Gu, Y. C.; Zheng, C. J.; She, Z. G.; Lin, Y. C. J.
Nat. Prod. 2011, 74, 629–633.
6
.
(a) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree,
P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561–1566. (b)
Isaka, M.; Yangchum, A.; Intamas, S.; Kocharin, K.; Jones, E. B.
G.; Kongsaeree, P.; Prabpai, S. Tetrahedron 2009, 65, 4396–4403.
Acuna, U. M.; Wittwer, J.; Ayers, S.; Pearce, C. J.; Oberlies, N.
H.; DE Blanco, E. J. Anticancer Res. 2012, 32, 2665-2671.
Sugawara, F.; Kim, K. W.; Kobayashi, K.; Yoshida, J. S.;
Murfushi, N.; Takahashi, N.; Strobel, G. A. Phytochemistry 1992,
7
8
.
.
3
1, 1987–1990.
9
1
.
Kim, K. W. Korean Journal of Weed Science, 1994, 14, 192-198.
0. (a) Barluenga, S.; Dakas, P. Y.; Ferandin, Y.; Meijer, L.;
Winssinger, N. Angew. Chem. Int. Ed. 2006, 45, 3951 –3954. (b)
Bajwa, N.; Jennings, M. P. Tetrahedron Letters 2008, 49, 390–
3
93. (c) Baird, L.J.; Timmer, M. S. M.; Paul H, P.; Teesdale-
Spittle, P.H.; Harvey, J. E.; J. Org. Chem. 2009, 74, 2271–2277.
d) Geng, X.; Danishefsky, S. J. Org. Lett., 2004, 6, 413-416. (e)
Calo, F.; Richardson, J.; Barrett, A, G. M. Org. Lett., 2009, 11,
910–4913. (f) Dakas, P-Y.; Jogireddy, R.; Valot, G.; Barluenga,
(
4
S.; Winssinger, N. Chem. Eur. J. 2009, 15, 11490 – 11497. (g)
Solorio, D. M; Belmore, K. A.; Michael P. Jennings, M. J. J. Org.
Chem. 2011, 76, 3898–3908. (h) Yang, Z.-Q.; Geng, X.; Solit, D.;
Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc.
2
004, 126, 7881–7889. (i) Winssinger, N.; Barluenga,S. Chem.
Commun. 2007, 22–36. (j) Srihari, P.; Mahankali, B.;
Rajendraprasad, K. Tetrahedron Letters 2012, 53, 56–58. (k)
Resorcylic acid lactones. Napolitano, C; Murphy, P V. Edited by
Janecki, T From Natural Lactones and Lactams 2014, 273-319. (l)
Hofmann, T., Altmann, K.-H. Comptes Rendus Chimie. 2008, 11,
1
318-1335. (m) Bräse, S., Encinas, A., Keck, J., Nising, C. F.
Chemical Reviews 2009, 109, 3903-3990. (n) Bolte, B.; Basutto, J.
A.; Bryan, C. S.; Garson, M. J.; Banwell, M. G.; Ward, J.S.; J.
Org. Chem. 2015, 80, 460−470.
1
1. (a) Jana, N.; Nanda, S. Eur. J. Org. Chem. 2012, 4313–4320. (b)
Gao, Y.; Liu, J.; Wang, L.; Xiao, M.; Du, Y. Eur. J. Org. Chem.
2
014, 2092–2098. (c) Mohapatra, D, K.; Reddy, D, S.;
Mallampudi, N. A.; Gaddam, J.; Polepalli, S.; Jainb, N.; Yadav, J.
S. Org. Biomol. Chem. 2014, 12, 9683-9695.
1
1
2. Lance, D. G.; Jones, J. K. N. Can. J. Chem., 1967, 45, 1533-1538.
3. Kamisuki, S.; Takahashi, S.; Mizushina, Y.; Hanashima, S.;
Kuramochi, K.; Kobayashi, S.; Sakaguchi, K.; Nakata, T.;
Sugawara, F. Tetrahedron 2004, 60, 5695–5700.
1
4. (a) Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508–524. (b)
Smith, A. B.; Ott, G. R.; J. Am. Chem. Soc. 1998, 120, 3935-3948.
(c) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am.
Chem. Soc. 2000, 122, 12894-12895. (d) Raghavan, S.; Babu, V.
S. Chem. Eur. J. 2011, 17, 8487 – 8494. (e) Fuerstner, A.; Funel,
J. A.; Tremblay, M.; Bouchez, L. C.; Nevado, C.; Waser, M.; Jens
Ackerstaff, Stimson, C. C. Chem. Commun. 2008, 2873–2875.
5. Sharma, G. V. M.; Kumar, K. R. Tetrahedron: Asymmetry, 2004,
1
1
1
5, 2323–2326.
6. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Letter
975, 16, 4467. (b) Birkett, S.; Ganame, D.; Hawkins, B. C.;
Meiries, S.; Quach, T.; Rizzacasa, M. A. Org. Lett. 2011, 13,
964–1967.
7. (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2003, 125, 30-31.
b) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124,
922-7923.
1
1
1
(
7
1
1
8. The E-isomer of the protodesilylated olefin was confirmed based
on coupling constant 15.9 Hz in 1H NMR.
9. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John
Wiley & Sons: New York, 1993, pp. 56–82. (b) Noyori, R.;
Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi,
H.; Akuragawa, S. J. Am. Chem. Soc. 1987, 109, 5856–5858.
0. (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, P.
Synlett 1998, 26–28. (b) Kocienski, P. J.; Lythgoe, B.; Ruston, S.;
J. Chem. Soc. Perkin Trans. 1 1978, 829 –834.
2

ACCEPTED MANUSCRIPT
Supporting Information
Convergent and Stereoselective Synthesis of Zeaenol
Rayala Naveen Kumar, H. M. Meshram*
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India, Tel.: +91 40
2
7191640; Fax: +91-40-27193275
E-mail: hmmeshram@yahoo.com
1
13
2
. H NMR and C NMR Spectra of All New Compounds
S2 – S43
S1

ACCEPTED MANUSCRIPT
S2

ACCEPTED MANUSCRIPT
S3

ACCEPTED MANUSCRIPT
S4

ACCEPTED MANUSCRIPT
S5

ACCEPTED MANUSCRIPT
S6

ACCEPTED MANUSCRIPT
S7

ACCEPTED MANUSCRIPT
S8

ACCEPTED MANUSCRIPT
S9

ACCEPTED MANUSCRIPT
S10

ACCEPTED MANUSCRIPT
S11

ACCEPTED MANUSCRIPT
S12

ACCEPTED MANUSCRIPT
S13

ACCEPTED MANUSCRIPT
S14

ACCEPTED MANUSCRIPT
S15

ACCEPTED MANUSCRIPT
S16

ACCEPTED MANUSCRIPT
S17

ACCEPTED MANUSCRIPT
S18

ACCEPTED MANUSCRIPT
S19