Stereoselective total synthesis of umuravumbolide

Article abstract of DOI:10.1002/ejoc.201100510

A simple and efficient stereoselective total synthesis of desacetylumuravumbolide (1a) and umuravumbolide (1b), starting from commercially available valeraldehyde has been described. The synthetic strategy involves a highly enantioselective zinc-mediated addition of protected 2 alkyn-1-ol to aldehyde, a Crimmins aldol reaction, and Horner-Wadsworth-Emmons olefination as key steps. A simple and efficient stereoselective total synthesis of umuravumbolide and desacetylumuravumbolide starting from commercially available valeraldehyde is described. The synthetic strategy involves a highly enantioselective zinc-mediated addition, a Crimmins aldol reaction, and Horner-Wadsworth-Emmons olefination as key steps.

Full text of DOI:10.1002/ejoc.201100510

FULL PAPER
DOI: 10.1002/ejoc.201100510
Stereoselective Total Synthesis of Umuravumbolide
Vanam Shekhar,[a] Dorigondla Kumar Reddy,[a] Sudina Purushotham Reddy,[a]
Peddikotla Prabhakar,[a] and Yenamandra Venkateswarlu*[a]
Keywords: Zinc / Aldol reactions / Aldehydes / Olefination
A simple and efficient stereoselective total synthesis of des-
acetylumuravumbolide (1a) and umuravumbolide (1b), start-
ing from commercially available valeraldehyde has been de-
scribed. The synthetic strategy involves a highly enantiose-
lective zinc-mediated addition of protected 2 alkyn-1-ol to
aldehyde, a Crimmins aldol reaction, and Horner–Wadsworth–
Emmons olefination as key steps.
from commercially available valeraldehyde. In our synthesis,
the stereogenic centers can easily be established by zinc-me-
diated addition of protected 2 alkyn-1-ol to the aldehyde
and a Crimmins aldol reaction. Our synthetic strategy for
the synthesis of 1b is outlined in Scheme 1. Desacetylumu-
ravumbolide (1a) could be derived from β-hydroxyamide 8
through Horner–Wadsworth–Emmons olefination, fol-
lowed by global deprotection of the silyl and meth-
oxymethyl (MOM) groups and concomitant cyclization.
Compound 8 could be obtained from aldehyde 7, which
could be obtained from valeraldehyde (2) by through the
highly enantioselective zinc-mediated addition of THP-pro-
tected propargyl alcohol 11 to 2.
Introduction
5,6-Dihydro-α-pyrone-containing natural products hav-
ing a substituted alkyl side chain at the C-6 position have
attracted much attention over the last decade due to the
Michael acceptor nature of the α,β-unsaturated α-pyrones
for the amino acid residues of receptors.[1] These pyrones
show various biological activities, including the inhibition
of HIV protease[2] and the inducing of apoptosis,[3] and they
act as antileukemic[4] and anticancer agents,[5] plant growth
inhibitors, pheromones, and antifeedent, antifungal, anti-
bacterial, and antitumor agents.[6] Compounds having the
5,6-dihydro-α-pyrone moiety, desacetylumuravumbolide
(1a) and umuravumbolide (1b),[7] were isolated from Tetra-
denia riparia of the Lamiaceae family from central and sou-
thern Africa. The structures of 1a and 1b were revised by
Davies–Coleman and Rivett. They determined the absolute
configuration on the basis of NMR and CD spectral studies
and also reported the optical rotations of these com-
pounds.[8] Our continued interest towards the total synthe-
sis of lactone-containing natural products[9] prompted us to
undertake the synthesis of demanding targets 1a and 1b. To
the best of our knowledge, there is only one report on the
synthesis of these natural products by Ramachandran et
al.[10] who used asymmetric reduction, allylboration, and
ring-closing metathesis.
Scheme 1. Retrosynthetic route for umuravumbolide.
Herein, we report a simple and practical synthesis of de-
sacetylumuravumbolide (1a) and umuravumbolide (1b)
Results and Discussion
[a] Organic Division I, Natural Products Laboratory,
Indian Institute of Chemical Technology,
Hyderabad 500607, India
As outlined in Scheme 2, the first stereocenter was gener-
ated by the highly enantioselective addition of propargyl
alcohol 11 to 2 in the presence of Et2Zn in toluene (1 mmol)
Fax: +91-040-27160512
E-mail: luchem@iict.res.in
4460
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4460–4464

Stereoselective Total Synthesis of Umuravumbolide
and a catalytic solution of (R)-BINOL (0.1 mmol), phenol
(0.1 mmol), Ti(iPrO)4 (0.25 mmol) in dry ether to give com-
pound 3 in 95% yield[11] with 93%ee. The enantiomeric pu-
rity was determined by HPLC analysis (see the Experimen-
tal Section for details). The secondary hydroxy group in
compound 3 was protected with tert-butyldiphenylsilyl
(TBDPS) chloride as TBDPS ether 4 in 93% yield. The
tetrahydropyranyl group in compound 4 was deprotected
with pyridinium p-toluenesulfonate (PPTS)/MeOH to give
compound 5 in 95%, which was oxidized with 2-iodoxyben-
zoic acid (IBX) in DMSO and dry dichloromethane (DCM)
to afford aldehyde 6 in 90% yield. Aldehyde 6 was con-
verted into required (Z)-olefinic aldehyde 7 in 85% yield
by hydrogenation using Lindlar’s catalyst in dry DCM. We
synthesized aldehyde 7 in five steps with an overall yield of
65%.
Scheme 3. Reagents and conditions: (a) 12, TiCl4, DIPEA, dry
DCM, –78 °C, 77%; (b) MOMCl, DIPEA, 7 h, 0 °C to r.t., 95%;
(c) 1. DIBAL-H, dry DCM, –78 °C, 5 min; 2. NaH/THF, –78 °C,
30 min, then (CF3CH2O)2P(O)CH2COOCH3, THF, 30–45 min,
82%; (d) 3 m HCl, THF (1:1), 3 h, r.t.; (e) Ac2O, pyridine, DCM,
18 h, 97%.
CHCl3)} in 97% yield (Scheme 3). The physical and spec-
troscopic data of 1a and 1b were in full agreement with
those of reported natural product.[8]
Scheme 2. Reagents and conditions: (a) 11, Et2Zn, (R)-BINOL,
Ti(OiPr)4, PhOH, 95%, 93%ee; (b) TBDPSCl, imidazole, dry
DCM, 6 h, r.t., 93%; (c) PPTS, MeOH, r.t., 95%; (d) IBX /DMSO,
CH2Cl2, 0 °C to r.t., 90%; (e) Lindlar‘s catalyst, DCM, H2, 8 h,
85%.
Conclusions
A stereoselective total synthesis of umuravumbolide from
valeraldehyde with a high overall yield of 22% has been
demonstrated. In our synthesis, the stereogenic centers can
be easily established by zinc-mediated addition of protected
2 alkyn-1-ol to the aldehyde and a Crimmins aldol reaction.
Aldehyde 7 was subjected to an aldol reaction with chiral
(S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone (12) in
the presence of N,N-diisopropylethylamine (DIPEA) and ti-
tanium tetrachloride in dry DCM under the Crimmins pro-
tocol[12] to give a mixture of diastereomers in 77% yield
(Scheme 3). The diastereomers of the β-hydroxy amide were
easily separable (syn/anti = 8.5:1.5). The diastereoselectivity
of the Crimmins aldol reaction was determined by HPLC
(see the Experimental Section for details). The hydroxy
group in 8 was protected as MOM ether 9 in 95% yield by
using DEIPA and MOMCl in dry DCM. Amide 9 was
Experimental Section
General Methods: All solvents and reagents were purified by stan-
dard techniques. Crude products were purified by column
chromatography on silica gel of 60–120 and 100–200 mesh. FTIR
treated with DIBAL-H to give the aldehyde, which was sub- spectra were measured with a Thermo Nicolet Nexus 670 spec-
trometer. Optical rotations were recorded with a Horiba high sensi-
tive polarimeter in a 10 mm cell. 1H and 13C NMR spectra were
recorded in CDCl3 solution with a Bruker Avance 300. Chemical
shifts were reported in parts per million with respect to internal
TMS. Mass spectra were acquired with a Micro mass Quattro
Micro API (Waters) mass spectrometer. HPLC chiral analyses were
performed with a Shimadzu LC-20 AT apparatus equipped with a
UV detector by using a 25 cm ϫ4.6 mm DAICEL Chiracel AD-H
column. HPLC were measured with an Agilent 1100 series appara-
tus equipped with a DAD detector by using 150 ϫ4.6 mm ZOR-
jected to Horner–Wadsworth–Emmons olefination by em-
ploying bis(2,2,2-trifluoromethyl)(methoxycarbonylmeth-
yl)phosphonate[13] to give cis-olefinic ester 10 in 82% yield.
With cis-olefinic ester 10 in hand, we proceeded further
to the one-pot deprotection of the protecting groups with
concomitant cyclization of the ester and alcohol functional-
ities with 3.0 m HCl/THF (1:1) at room temperature to af-
ford 1a {[α]2D5 = –5.4 (c = 1, CHCl3)} in 60% yield. Further,
in a separate experiment, 1a was acetylated by using acetic
anhydride/pyridine to afford 1b {[α]2D5 = +33.4 (c = 1, BAX SBC-3 columns.
Eur. J. Org. Chem. 2011, 4460–4464
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Shekhar, D. K. Reddy, S. P. Reddy, P. Prabhakar, Y. Venkateswarlu
FULL PAPER
(4S)-1-(Tetrahydro-2H-pyran-2-yloxy)oct-2-yn-4-ol (3): A solution
of Et2Zn (1.1 m) in toluene (10 mL, 10.0 mmol) was added at room
temperature to a solution of 11 (1.24 g, 10.0 mmol) in dry toluene
(1 mL), and the mixture was heated at reflux for 1 h. A catalyst
solution of (R)-BINOL (286 mg, 1.0 mmol), phenol (94 mg,
1.0 mmol), and Ti(iPrO)4 (0.74 mL, 2.5 mmol) in anhydrous Et2O
(3 mL) was stirred for 30 min. This solution was added to the reac-
tion mixture, and the mixture was stirred for 1 h at room tempera-
ture before adding valeraldehyde (2; 0.26 mL, 2.5 mmol). The entire
reaction mixture was stirred for 4 h at room temperature. After
completion of the reaction, the reaction was quenched with NH4Cl
(15 mL) and extracted with ethyl acetate (2ϫ10 mL). The com-
bined organic layer was washed with 2 n HCl (2ϫ5 mL), NaHCO3
(2ϫ5 mL), and brine (10 mL), dried with MgSO4, and evaporated
under reduced pressure. Thus obtained crude residue was purified
over silica gel (CH2Cl2/MeOH, 99:1) to give 3 (504 mg, 95%) as a
OH), 1.71–1.62 (m, 2 H), 1.45–1.22 (m, 4 H), 1.06 [s, 9 H,
Si(CH3)3], 0.88 (t, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.0, 135.8, 134.7,134.1, 129.6, 129.4, 127.5, 127.1,
87.3, 83.0, 63.8, 51.0, 37.9, 27.0, 26.9, 26.5, 19.3, 14.0·ppm. MS
(ESI): m/z = 398 [M + NH4]+.
(4S)-4-(tert-Butyldiphenylsilyloxy)oct-2-ynal (6): To a stirred solu-
tion of IBX (635 mg, 2.3 mmol) in dry DMSO (5 mL) was added
a solution of 5 (0.35 g, 1.5 mmol) in DCM (10 mL) at room tem-
perature, and the mixture was stirred for 5 h at room temperature.
After completion of the reaction, the mixture was filtered, diluted
with water (5 mL), and extracted into DCM (2ϫ10 mL). The com-
bined organic layer was washed with brine (5 mL), dried (Na2SO4),
and concentrated under reduced pressure to give the crude alde-
hyde, which was purified by column chromatography (hexane/
EtOAc, 9:1) to give 6 (519 mg, 90%) as a colorless liquid. [α]2D5
=
–23.5 (c = 2, CHCl ). IR (neat): ν = 2956, 2932, 2859, 2208, 1670,
˜
colorless oil. [α]2D5 = –6.76 (c = 2.25, CHCl ). IR (neat): ν = 3414,
3
˜
3
1109, 702 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.01 (s, 1 H,
CHO), 7.73–7.57 (m, 4 H, ArH), 7.48–7.28 (m, 6 H, ArH), 4.52–
4.45 (m, 1 H, CHOTBDPS), 1.78–1.64 (m, 1 H), 1.54–1.19 (m, 5
H), 1.09 [s, 9 H, Si(CH3)3], 0.86 (t, J = 6.8 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 176.5, 135.9, 135.7, 132.9, 132.8,
129.9, 129.8, 127.79, 127.5, 97.8, 84.1, 63.6, 37.1, 26.8, 26.5, 22.2,
19.2, 13.8 ppm.
2942, 2864, 1623, 1120, 1025 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 4.78 (dd, J = 3.0, 0.8 Hz, 1 H, OCHO), 4.35 (t, J = 6.0 Hz, 1
H, CHOH), 4.25 (d, J = 1.5 Hz, 1 H, OCHC), 4.23 (d, J = 2.3 Hz,
1 H, OCHC), 3.84–3.76 (m, 1 H, CϵCHOC), 3.55–3.48 (m, 1 H,
CϵCHOC), 1.88–1.31 (m, 12 H), 0.93 (t, J = 6.8 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 96.7, 87.2, 80.5, 62.3, 62.0,
54.22, 37.3, 30.1, 27.2, 25.2, 22.2, 18.9, 13.9 ppm. HRMS (ESI):
calcd. for C13H22NaO3 [M + Na]+ 249.1461; found 249.1472.
HPLC (DAICEL Chiralpak AD-H, hexane/iPrOH = 90:10, flow
rate = 1.0 mL/ min, λ = 210 nm): tR = 10.3 (major), 11.7 min
(minor); 93%ee.
(Z,4S)-4-(tert-Butyldiphenylsilyloxy)oct-2-enal (7): To a solution of
aldehyde 6 (1.88 g, 5.0 mmol) in dry DCM (20 mL) was added
Lindlar’s catalyst (0.5 g), and the mixture was stirred under a hy-
drogen atmosphere. The reaction was monitored by TLC. After
completion of the reaction (10 h), the reaction mixture was filtered
through a silica gel pad; the solvent was removed, and the residue
was purified by silica gel column chromatography (hexane/EtOAc,
9:1) to afford 7 (1.6 g, 85%) of as a liquid. [α]2D5 = +15.1 (c = 1.65,
tert-Butyldiphenyl[(4S)-1-(tetrahydro-2H-pyran-2-yloxy)oct-2-yn-4-
yloxy]silane (4): To a cooled (0 °C) solution of 3 (1.4 g, 6.2 mmol)
and imidazole (1.3 g, 19.1 mmol) in dry DCM (30 mL) was added
tert-butyldiphenylsilyl chloride (2.0 g, 7.44 mmol) dropwise, and
the mixture was stirred for 4 h. After the completion of reaction,
the reaction mixture was diluted with water (20 mL) and extracted
into DCM (3ϫ30 mL). The combined organic layer was washed
with brine (10 mL), dried with anhydrous Na2SO4, and concen-
trated under vacuum to furnish the crude residue, which was puri-
fied by silica gel column chromatography (hexane/EtOAc, 5:95) to
give 4 (2.6 g, 93%) as a yellow liquid. [α]2D5 = –46.99 (c = 2.5,
CHCl ). IR (neat): ν = 2957, 2932, 2859, 1688, 1466, 1428, 1109,
˜
3
703 cm–1. H NMR (300 MHz, CDCl3): δ = 9.29 (d, J = 8.0 Hz, 1
1
H, CHO), 7.65–7.57 (m, 4 H, ArH), 7.42–7.30 (m, 6 H, ArH), 6.39
(dd, J = 11.2, 8.8 Hz, 1 H, CH=C), 5.64 (dd, J = 11.2, 7.2 Hz, 1
H, =CHCHO), 4.92 (q, J = 15.2, 6.4 Hz, 1 H, CHOTBDPS), 1.75–
1.45 (m, 2 H), 1.28–1.17 (m, 4 H), 1.06 [s, 9 H, Si(CH3)3], 0.86 (t,
J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
190.4, 153.1, 135.7, 135.6, 133.3, 133.2, 130.8, 129.9, 129.4, 128.1,
127.6, 127.5, 68.8, 37.4, 26.8, 22.3, 19.1, 13.8 ppm.
CHCl ). IR (neat): ν = 2936, 2859, 1428, 1112, 1026, 703 cm–1. 1H
˜
3
NMR (300 MHz, CDCl3): δ = 7.74–7.64 (m, 4 H, ArH), 7.41–7.30
(m, 6 H, ArH), 4.64 (dt, J = 9.8, 6.8, 3.0 Hz, 1 H, OCHO), 4.34
(tt, J = 1.5 Hz, 1 H, CHOTBDPS), 4.07 (d, J = 2.3 Hz, 2 H,
OCHC), 3.79–3.69 (m, 1 H, CϵCHOC), 3.49–3.40 (m, 1 H,
CϵCHOC), 1.69–1.46 (m, 6 H), 1.42–1.19 (m, 4 H), 1.06 [s, 9 H,
Si(CH3)3], 0.86 (t, J = 6.79 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 136.0, 135.8, 135.3, 133.7, 129.6, 129.4, 127.5, 127.3,
96.4, 87.3, 80.6, 63.8, 61.9, 54.1, 38.0, 30.2, 27.0, 26.9, 25.3, 22.3,
19.2, 19.0, 14.0 ppm. MS (ESI): m/z = 487 [M + Na]+.
(3R,6S,Z)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-6-tert-butyldi-
phenylsilyloxy]-3-hydroxydec-4-en-1-one (8): To cooled (0 °C) solu-
tion of 12 (0.6 mmol) in dry CH2Cl2 (6 mL) was added titani-
um(IV) chloride (1.32 mmol, 0.2 mL) dropwise, and the solution
was allowed to stir for 5 min, after which the solution turned yellow
in color. Then DIPEA (0.6 mmol, 0.11 mL) was added. The yellow
slurry or suspension turned dark red and was stirred for 20 min at
0 °C. To this dark red solution was added 7 (0.55 mmol, 200 mg)
in dry DCM (10 mL) dropwise, and the reaction mixture was
stirred for 1 h at 0 °C. After completion of the reaction, the reac-
tion was quenched with ammonium chloride solution (6 mL) and
then extracted into DCM (3ϫ10 mL). The combined organic layer
was dried with anhydrous Na2SO4 and concentrated under reduced
pressure to yield a crude residue, which was purified by silica gel
column chromatography (hexane/EtOAc, 8:2) to afford 8 (217 mg,
66%) along with anti-8a (37 mg, 11%). [α]2D5 = –15.14 (c = 1.75,
(4S)-4-(tert-Butyldiphenylsilyloxy)oct-2-yn-1-ol (5): To a cooled
(0 °C) solution of compound 4 (2 g, 4.4 mmol) in methanol
(10 mL) was added a catalytic amount of PPTS (30 mg), and the
mixture was stirred for 5 h. After completion of the reaction, the
reaction was quenched with saturated NaHCO3 and extracted into
ethyl acetate (3 ϫ 25 mL). The combined organic extract was
washed with brine, dried with anhydrous Na2SO4, and evaporated
under reduced pressure to give a crude residue, which was purified
by silica gel column chromatography (hexane/EtOAc, 8:2) to afford
pure compound 5 (1.55 g, 95%) as a clear liquid. [α]2D5 = –52.8 (c
CHCl ). IR (neat): ν = 3447, 2930, 2857, 1699, 1634, 1035,
˜
3
702 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.74–7.63 (m, 4 H,
ArH), 7.46–7.27 (m, 11 H, ArH), 5.62–5.46 (m, 1 H, CH=C), 5.36–
5.15 (m, 2 H, =CHCHO, NCHBn), 4.57–4.32 [m, 2 H,
(CHOTBDPS, CHOH)], 3.40–3.29 (m, 1 H, CHS), 3.25–3.14 [m, 2
H, (CHS, CHPh)], 3.04–2.98 [m, 2 H, (CHPh, CHCO)], 2.92–2.83
= 1.75, CHCl ). IR (neat): ν = 3376, 2933, 2860, 1427, 1109, 1074,
˜
3
702 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.75–7.65 (m, 4 H,
ArH), 7.40–7.30 (m, 6 H, ArH), 4.36 (tt, J = 1.5 Hz, 1 H,
CHOTBDPS), 3.95 (dd, J = 3.7 Hz, 2 H, CH2OH), 2.03 (s, 1 H,
4462
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Eur. J. Org. Chem. 2011, 4460–4464

Stereoselective Total Synthesis of Umuravumbolide
(m, 1 H, CHCO), 2.27 (s, 1 H, OH), 1.48–1.37 (m, 1 H),1.33–1.15
(m, 5 H), 1.04 [s, 9 H, Si(CH3)3], 0.85 (t, J = 6.7 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 201.1, 171.4, 136.4, 136.1,
135.9, 135.8, 134.7, 134.1, 134.2, 129.6, 129.3, 128.8, 128.4, 127.5,
H, COCH3), 3.18 (s, 3 H, OCH3), 2.39–2.27 (m, 2 H,
CH2CH=CH), 1.56–1.40 (m, 2 H), 1.38–1.1 (m, 4 H), 1.03 [s, 9 H
Si(CH3)3], 0.78 (t, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 150.8, 138.4, 136.1, 136.0, 129.5, 129.4, 127.5, 127.3,
127.4, 127.2, 69.3, 68.4, 63.7, 45.3, 38.0, 36.7, 32.0, 27.1, 26.9, 126.5, 121.0, 93.5, 73.5, 69.3, 55.4, 51.4, 41.6, 38.5, 38.1, 29.7, 27.0,
22.67, 19.2, 14.06 ppm. HRMS (ESI): calcd. for C36H45NNaO3S2Si 26.6, 26.9, 22.6, 19.3, 14.0 ppm. MS (ESI): m/z = 547 [M + Na]+.
[M + Na]+ 654.2502; found 654.2520. HPLC (ZORBAX SBC-3,
acetonitrile/water = 70:30, flow rate = 1.0 mL/ min, λ = 210 nm):
tR = 10.9 (major, 85%), 9.9 min (minor, 15%).
Desacetylumuravumbolide (1a): To a solution of 10 (130 mg,
0.27 mmol) was added 3 m HCl/THF (1:1, 2 mL of 3 m HCL +
2 mL of THF), and the solution was stirred for 3 h at room tem-
perature. After completion of the reaction, the reaction medium
was washed with sat. NaHCO3 solution and extracted into EtOAc.
The respective organic layer was washed with brine, dried with an-
hydrous Na2SO4, and concentrated to give a crude residue, which
was purified by silica gel column chromatography (hexane/EtOAc,
6:4) to afford 1a (30 mg, 60%). [α]2D5 = –5.4 (c = 1, CHCl3). IR
(Z,3R,6S)-1-[(4S)-4-Benzyl-2-thioxothiazolidin-3-yl]-6-(tert-butyldi-
phenylsilyloxy)-3-(methoxymethoxy)dec-4-en-1-one (9): To a stirred
solution of 8 (470 mg, 0.80 mmol) and DIPEA (0.43 mL,
2.4 mmol) in dry DCM (20 mL) was added MOMCl (0.13 mL,
1.6 mmol) at 0 °C, and the mixture was stirred for 12 h at room
temperature. After completion of the reaction as monitored by
TLC, water was added, and the reaction mixture was extracted into
DCM (3ϫ20 mL) and dried with anhydrous Na2SO4. The solvent
was removed under reduced pressure to give a crude residue, which
was purified by silica gel column chromatography (hexane/EtOAc,
9:1) to afford 9 (480 mg, 95%) as a colorless oil. [α]2D5 = –1.11 (c =
(neat): ν = 3429, 2924, 2855, 1726, 1377, 1243, 1082 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 6.88 (m, 1 H, CH=CHCOO), 6.0 (dd, J =
9.8, 2.2 Hz, 1 H, =CHCOO), 5.60–5.73 (m, 2 H, CH=CH), 5.25–
5.36 (m, 1 H, CHOCO), 4.33–4.47 (m, 1 H, CHOH), 2.34–2.51 (m,
2H CH2CH=CH), 2.2 (s, 1 H, OH), 1.45–1.70 (m, 2 H), 1.20–1.42
(m, 4 H), 0.88 (t, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 163.8, 144.9, 137.9, 127.4, 121.4, 73.7, 67.7, 36.8, 29.9,
27.5, 22.6, 14.0 ppm. HRMS (ESI): calcd. for C12H19O3 [M + H]+
211.1329; found 211.1323.
0.77, CHCl ). IR (neat): ν = 2930, 2858, 1690, 1350, 1160, 1047,
˜
3
702 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.75–7.62 (m, 4 H,
ArH), 7.42–7.27 (m, 11 H, ArH), 5.74 (dd, J = 11.3, 9.0 Hz, 1 H,
CH=C), 5.33–5.21 [m, 2 H, (=CHCHOMOM, NCHBn], 4.75–4.54
[m, 2 H, (CHOTBDPS, CHOMOM)], 4.25 (s, 2 H, OCH2O), 3.63–
3.52 (m, 1 H, CHS), 3.42–3.26 [m, 2 H, (CHS, CHPh)], 3.23 (s, 3
H, OCH3), 3.10–2.95 [m, 2 H, (CHPh, CHCO)], 2.89–2.83 (m, 1
H, CHCO), 1.46–1.38 (m, 1 H), 1.32–1.10 (m, 5 H), 1.05 [s, 9 H,
Si(CH3)3], 0.85 (t, J = 6.7 Hz 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 201.1, 170.5, 137.5, 137.2, 136.0, 135.9, 129.6, 129.5,
129.4, 129.3, 128.8, 127.6, 127.5, 127.1, 127.4, 127.2, 94.3, 69.7,
68.6, 68.1, 55.6, 44.5, 37.8, 36.4, 32.1, 27.0, 26.8, 22.5, 19.3,
14.0 ppm. HRMS (ESI): calcd. for C38H49NNaO4S2Si [M + Na]+
698.2764; found 698.2789.
Umuravumbolide (1b): To solution of compound 1a (52 mg,
0.25 mmol) and pyridine (80 mg, 1 mmol) in DCM (1 mL) was
added Ac2O (0.05 g, 0.5 mmol), and the solution was stirred for
18 h. After completion of the reaction, the reaction was diluted
with cold water and extracted into DCM (3ϫ15 mL). The com-
bined extract was dried with anhydrous Na2SO4 and concentrated
to yield a crude residue, which was purified by silica gel chromatog-
raphy (hexane/EtOAc, 8:2) to yield 1b (61 mg, 97%). [α]2D5 = +33.4
(c = 1, CHCl ). IR (neat): ν = 2929, 2860, 1747, 1730, 1242 cm–1.
˜
3
1H NMR (300 MHz, CDCl3): δ = 6.88 (m, 1 H, CH=CHCOO),
6.01 (dd, J = 9.8, 2.2 Hz, 1 H, =CHCOO), 5.71 (dd, J = 11.1,
8.0 Hz, 1 H, CH=CH), 5.31–5.56 (m, 3 H, =CH, CHOCO, CHOC-
OCH3), 2.28–2.57 (m, 2 H, CH2CH=CH), 2.02 (s, 3 H, COCH3),
1.44–1.75 (m, 2 H), 1.20–1.43 (m, 4 H), 0.87 (t, J = 6.9 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.1, 163.4, 144.2,
131.7, 130.0, 121.7, 74.0, 69.5, 34.3, 30.1, 27.3, 22.5, 22.2, 17.0,
14.0 ppm. MS (ESI): m/z = 253 [M + H]+.
Methyl (2Z,5R,6Z,8S)-8-(tert-butyldiphenylsilyloxy)-5-(meth-
oxymethoxy)dodeca-2,6-dienoate (10): To a cooled (–78 °C) solu-
tion of 9 (330 mg, 0.52 mmol) in dry CH2Cl2 (6 mL) was added
DIBAL-H (0.46 mL, 0.471 mmol, 20% in toluene), and the reac-
tion mixture was allowed to stir at –78 °C for 5–10 min. After com-
pletion of the reaction, the reaction was quenched with sodium
potassium tartarate solution (1 mL). The reaction mixture was
passed through a short pad of Celite. The filtrate was concentrated
to afford the crude aldehyde. This crude aldehyde was directly used
for the next reaction. To a cooled (0 °C) stirred suspension of NaH
(36 mg, 1.55 mmol) in dry THF (6 mL) under a nitrogen atmo-
sphere was added bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)
phosphonate (270 mg, 0.84 mmol) in dry THF (3 mL), and the
mixture was stirred for 30 min at 0 °C. The reaction temperature
was brought to –78 °C, and then a solution of aldehyde (351 mg,
0.77 mmol) in dry THF (5 mL) was added dropwise and stirred for
1 h. After completion of the reaction, the reaction was diluted with
Et2O (5 mL) and quenched by the slow addition of water (3 mL)
and extracted into Et2O (3ϫ10 mL). The organic extract was
washed with brine solution, dried with anhydrous Na2SO4, and
concentrated under reduced pressure to yield a crude residue, which
was purified by silica gel column chromatography (hexane/EtOAc,
9:1) to give 10 (320 mg, 82%) as a viscous liquid. [α]2D5 = +43.1 (c
= 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.72–7.64 (m, 4 H,
ArH), 7.44–7.32 (m, 6 H, ArH), 6.86 (dd, J = 11.5, 8.3 Hz, 1 H,
CH=CHCOCH3), 5.78 (dd, J = 11.5, 8.6 Hz, 1 H, =CHCOCH3),
5.71 (d, J = 10.6 Hz, 1 H, CH=C), 5.16 (dt, J = 10.6 Hz, 1 H,
=CHCHOMOM), 4.45–4.40 (m, 1 H, CHOTBDPS), 4.12 (s, 2 H,
OCH2O), 3.90 (dd, J = 9.6, 4.8 Hz, 1 H, CHOMOM), 3.70 (s, 3
Acknowledgments
The authors are thankful to the Council of Scientific and Industrial
Research, New Delhi, India for financial support.
[1] S. B. Buck, C. Hardouin, S. Ichikawa, D. R. Soenen, C. M.
Gauss, I. Hwang, M. R. Swingle, K. M. Bonness, R. E. Honk-
anen, D. L. Boger, J. Am. Chem. Soc. 2003, 125, 15694–15695.
[2] K. R. Romines, R. A. Chrusciel, Curr. Med. Chem. 1995, 2,
825–838.
[3] S. H. Inayat-Hussain, B. O. Annuar, L. B. Din, N. Taniguchi,
Toxicol. Lett. 2002, 131, 153–159.
[4] H. Kikuchi, K. Sasaki, J. Sekiya, Y. Maeda, A. Amagai, Y.
Kubohara, Y. Ohsima, Bioorg. Med. Chem. 2004, 12, 3203–
3214.
[5] A. D. Fatima, L. K. Kohn, M. A. Antonio, J. E. Carvalho,
D. R. A. Pilli, Bioorg. Med. Chem. 2005, 13, 2927–2933.
[6] M. T. Davies-Coleman, D. E. A. Rivett, Fortschr. Chem. Org.
Naturst. 1989, 55, 1–35.
[7] L. Van Puyvelde, S. Dube, E. Uwimana, C. Uwera, R. A.
Dommisse, E. L. Esmans, O. Van Schoor, A. J. Vlietinck, Phy-
tochemistry 1979, 18, 1215–1218.
Eur. J. Org. Chem. 2011, 4460–4464
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4463

V. Shekhar, D. K. Reddy, S. P. Reddy, P. Prabhakar, Y. Venkateswarlu
FULL PAPER
[8] M. T. Davies-Coleman, D. E. A. Rivett, Phytochemistry 1995,
38, 791–792.
[11]
a) G. Gao, D. Moore, R. G. Xie, L. Pu, Org. Lett. 2002, 4,
4143–4146; b) Z. B. Li, L. Pu, Org. Lett. 2004, 6, 1065–1068;
c) Y. Georges, Y. Allenbach, X. Ariza, J. M. Campagne, J. Org.
Chem. 2004, 69, 7387–7390.
a) M. T. Crimmins, B. W. King, E. A. Tabet, K. Chaudhary, J.
Org. Chem. 2001, 66, 894–902; b) M. B. Hodge, H. F. Olivo,
Tetrahedron 2004, 60, 9397–9403; c) M. T. Crimmins, K.
Chaudhary, Org. Lett. 2000, 2, 775–777.
[9] a) V. Shekhar, D. K. Reddy, V. Suresh, D. C. Babu, Y. Venkates-
warlu, Tetrahedron Lett. 2010, 51, 946–948; b) D. K. Reddy, V.
Shekhar, T. S. Reddy, S. P. Reddy, Y. Venkateswarlu, Tetrahe-
dron: Asymmetry 2009, 20, 2315–2319; c) D. K. Reddy, V. Shek-
har, P. Prabhakar, B. C. Babu, B. Siddhardha, U. S. N. Murthy,
Y. Venkateswarlu, Eur. J. Med. Chem. 2010, 45, 4657–4663; d)
M. Narasimhulu, A. SaiKrishna, J. Venkateswara Rao, Y. Ven-
kateswarlu, Tetrahedron 2009, 65, 2989–2994.
[12]
[13] K. J. Ando, Org. Chem. 1997, 62, 1934–1939.
Received: April 12, 2011
[10] V. M Ram Reddy, J. P. Rearick, N. Hoch, V. P. Ramachandran,
Org. Lett. 2001, 3, 19–20.
Published Online: June 17, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4460–4464