A formal synthesis of herboxidiene/GEX1A

Article abstract of DOI:10.1002/ejoc.201402235

A formal synthesis of herboxidiene/GEX 1A is described. This approach demonstrates successful application of the Prins cyclization for the construction of the tetrahydropyran core of the target molecule. The chirality of the side chain has been established through the Sharpless asymmetric dihydroxylation and Evan's alkylation. The olefin cross-metathesis was applied to couple both key fragments. Copyright

Full text of DOI:10.1002/ejoc.201402235

FULL PAPER
DOI: 10.1002/ejoc.201402235
A Formal Synthesis of Herboxidiene/GEX1A
Jhillu S. Yadav,*[a] G. Madhusudhan Reddy,[a] S. Rehana Anjum,[a] and B. V. Subba Reddy[a]
Keywords: Total synthesis / Asymmetric synthesis / Cyclization / Metathesis / Herboxidiene
A formal synthesis of herboxidiene/GEX 1A is described.
This approach demonstrates successful application of the
Prins cyclization for the construction of the tetrahydropyran
core of the target molecule. The chirality of the side chain
has been established through the Sharpless asymmetric
dihydroxylation and Evan’s alkylation. The olefin cross-
metathesis was applied to couple both key fragments.
proteins in plasma and transport them into cells to clear
the elevated level of plasma cholesterol.[4]
Introduction
A herbicidal polyketide, herboxidiene (1) was isolated
from the Streptomyces chromofuscus A7847 cluster in 1992
(Figure 1).[1,2] Subsequently, herboxidiene was re-isolated
along with five structurally related antibiotics named as
GEX1 from the culture broth of Streptomyces sp.[3] Among
them, a major compound was identified as herboxidiene
and it was named as GEX1A, which exhibits potent herbici-
dal[1] and antitumor activity (TAN-1609) against various
cancer cell lines such as epidermoid carcinoma A431 cells,
human lung carcinoma A549 cells and human colon carci-
noma DLD-1 cells.[3] Other active components were named
as GEX1 Q1-Q5 based on the order of elution from ODS
HPLC column. GEX1A also shows a significant in vivo
cytotoxicity against SVT2 murine fibrosarcoma by affecting
cell cycle progression.
Owing to its attractive biological properties and syntheti-
cally challenging structural features such as trisubstituted
tetrahydropyran core, conjugated diene moiety, and poly-
oxygenated side chain, various approaches have been de-
vised to synthesize GEX1A.[5] The first total synthesis of
herboxidiene 1 was accomplished by the Kocienski group[5a]
in 1999. Later on, a few more syntheses of this natural
product were reported that employed various strategic ap-
proaches.
Results and Discussion
In recent years, the Prins cyclization reaction has
emerged as a powerful synthetic tool for the stereoselective
synthesis of tetrahydropyran scaffolds.[6] Inspired by its ver-
satility in natural products synthesis, we attempted the for-
mal synthesis of GEX1A by using Prins cyclization as a key
step to construct its tetrahydropyran core.
Our retrosynthetic analysis (Scheme 1) reveals the dis-
connection of target molecule 1 at the C9–C10 junction
leading to tetrahydropyran core 2 and oxygenated side-
chain 3. The diene part of side-chain 3 can be prepared
by olefin cross-metathesis reaction. A variant of the Prins
cyclization reaction developed by our group[7] was proposed
to construct tetrahydropyran ring 2 through coupling of al-
dehyde 5 with a homoallylic alcohol 4, which could in turn
be prepared by enantioselective crotylation of aldehyde 6.
The methyl chiral center of side chain 3 could be acquired
by Evan’s alkylation. Furthermore, the chiral diol moiety
could be constructed by asymmetric dihydroxylation of
conjugated ester 9, which could in turn could be acquired
from readily available (S)-Roche ester 10.
Figure 1. GEX1 family of polyketides.
It also activates the gene transcription of low-density li-
poprotein receptors, which bind to the cholesterol-rich lipo-
[a] Natural Products Chemistry Division, CSIR – Indian Institute
of Chemical Technology,
Accordingly, the synthesis of a target molecule 1 began
from aldehyde 6. A highly enantioselective crotylation of
aldehyde 6 with crotyl donor 11 in the presence of p-
TSA·H2O in CH2Cl2 gave corresponding homoallylic
alcohol 12 in 86% yield and Ͼ99% ee.[8]
Tarnaka, Hyderabad 500007, A.P., India
E-mail: yadavpub@iict.res.in
www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402235.
Eur. J. Org. Chem. 2014, 4389–4397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. S. Yadav, G. M. Reddy, S. R. Anjum, B. V. S. Reddy
FULL PAPER
(2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO)/bis(acet-
oxy)iodobenzene (BAIB) conditions followed by esterifica-
tion with freshly generated CH2N2 from N-nitroso-N-meth-
ylurea gave ester 16. The pivaloyl ester of 16 was then hy-
drolyzed in the presence of K2CO3 in MeOH to afford
alcohol 17 in 88% yield.
The hydroxy group of 17 was then oxidized with Dess–
Martin periodinane[11] in CH2Cl2 to furnish the corre-
sponding aldehyde, which was subjected to Wittig ole-
fination with Ph3PCH3Br by using nBuLi in tetra-
hydrofuran (THF) to afford required fragment 2 in 75%
yield (Scheme 3).
Scheme 1. Retrosynthetic analysis of herboxidiene.
The coupling of monobenzyl ether of homoallylic diol 12
with aldehyde 5 under Prins conditions gave the tetra-
hydropyran in poor yield. Therefore, we next attempted the
above Prins reaction with homoallylic diol 4 instead of
monobenzyl ether 12. Eventually, the monobenzyl ether 12
was subjected to debenzylation[9] to give homoallylic diol 4
in quantitative yield. Further treatment of diol 4 with alde-
hyde 5 in presence of CeCl3·7H2O/LiI in dichloroethane
(DCE) under reflux conditions afforded 4-iodotetrahydro-
pyran 13 (Scheme 2) in 76% yield with 97% de (by HPLC
analysis).
Scheme 3. Synthesis of fragment 2.
Next we focused our attention towards the construction
of side-chain 3. Accordingly, the hydroxy group of (S)-Ro-
che ester 10 was protected as its benzyl ether 18 by using
benzyl trichloroacetimidate in the presence of a catalytic
amount of triflic acid.[12] Partial reduction[13] of 18 with
diisobutylaluminum hydride (DIBAL-H) in CH2Cl2 at
–78 °C afforded the corresponding aldehyde, which was
then subjected to Wittig reaction with Ph3PCHCOOEt in
benzene under reflux conditions to give unsaturated ester 9
as a mixture of cis/trans isomers (5:95) in 92% yield, which
could be separated by column chromatography.
Sharpless asymmetric dihydroxylation[14] of 9 by using
AD-mix β in the presence of MeSO2NH2 in tBuOH/H2O
(1:1) at 0 °C afforded diol 19 as an inseparable dia-
stereomeric mixture (93:7). The diastereomers could be sep-
arated by column chromatography after protecting the diol
as its acetonide by using 2,2-dimethoxypropane (2,2-DMP)
in the presence of p-toluenesulfonic acid (p-TSA) in CH2Cl2
Scheme 2. Prins cyclization reaction.
The advantage of the CeCl3·7H2O/LiI reagent system to furnish required diastereomer 20 in 85% yield. Re-
over TFA or BF3·Et2O, as in classical Prins cyclization reac- duction of ester 20 by using DIBAL-H in CH2Cl2 gave
tions, is that the reaction proceeds smoothly under neutral alcohol 21, which was then protected as tosylate 22 in 90%
conditions even in the presence of acid-labile protecting yield (Scheme 4). Cleavage of the acetonide in 22 followed
groups.
by treatment with K2CO3 in MeOH gave epoxide 24. Pro-
Reductive dehalogenation[10] of iodide 13 was carried out tection of the hydroxy group of 24 with MeI in the presence
in the presence of sodium borohydride in dimethyl sulfoxide of NaH in THF afforded methyl ether 25 in 88% yield.
(DMSO) at 80 °C to furnish tetrahydropyran derivative 14 During methylation special care was taken to prevent the
in 90% yield. Oxidation of alcohol 14 to acid 15 under competing Payne rearrangement[15] by maintaining the re-
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Eur. J. Org. Chem. 2014, 4389–4397

A Formal Synthesis of Herboxidiene/GEX1A
action temperature constantly at 0 °C and also by portion- yield. Debenzylation of 27 with Pd/C under H2 atmosphere
wise addition of NaH.
in EtOAc gave alcohol 8 in 95% yield.
Oxidation of alcohol 8 with 2-iodoxybenzoic acid (IBX)/
DMSO in CH2Cl2 followed by Wittig reaction with
Ph3PCH(CH3)CO2Et in benzene afforded unsaturated ester
28 as a mixture of cis/trans-isomers (8:92), which could be
separated by column chromatography. Reduction of ester
28 with DIBAL-H in CH2Cl2 at 0 °C gave allylic alcohol 7
in 78% yield. The reaction was carefully monitored and the
temperature of the reaction mixture was maintained uni-
formly at 0 °C to prevent cleavage of the TBS ether. Conver-
sion of alcohol 7 into iodide 29 (Scheme 5) followed by
Evans’ alkylation[16] with enolate 30 afforded product 31 in
56% yield (2 steps) as a single diastereomer.
The reductive cleavage of the chiral auxiliary of 31 by
using LiBH4 in MeOH at room temperature afforded
alcohol 32 in 80% yield. Oxidation of the free hydroxy
group followed by Wittig olefination with Ph3PCH3Br and
nBuLi in THF gave desired fragment 3 in 72% yield
(Scheme 6).
Scheme 4. Synthesis of intermediate of 22.
Regioselective ring-opening of the epoxide with LiAlH4
in THF at 0 °C followed by tert-butyldimethylsilyl (TBS)
protection of the newly formed hydroxy group with TBSCl
in the presence of imidazole furnished TBS-ether 27 in 90%
Scheme 6. Completion of fragment 3.
With both fragments 2 and 3 in hand, we attempted the
cross metathesis of olefin 2 with diene 3.[5f] The reaction
proceeded smoothly in CH2Cl2 in the presence of Hoveyda–
Grubbs II catalyst at ambient temperature to afford 33 in
76% yield with 14:1 E/Z selectivity (calculated from the 1H
NMR spectrum) along with self-coupled product diene 2.
The spectroscopic data of 33 was consistent with the data
reported in literature.[5f] The total synthesis of herboxidiene
(1) can be achieved by using a known procedure[5f] from
fragment 33 in 3 steps involving TBS deprotection, stereose-
lective epoxidation and ester hydrolysis (Scheme 7).
Scheme 7. Coupling of fragments 2 and 3.
Conclusions
We have developed a convergent and expedient route for
the formal synthesis of herboxidiene involving a linear se-
Scheme 5. Synthesis of allylic iodide 29.
Eur. J. Org. Chem. 2014, 4389–4397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4391

J. S. Yadav, G. M. Reddy, S. R. Anjum, B. V. S. Reddy
[α]2D5 = –4.4 (c = 3.0, CHCl ). IR (neat): ν
= 3354, 3023, 2935,
FULL PAPER
˜
quence of 22 steps. This approach mainly demonstrates the
versatility of the Prins cyclization reaction in the construc-
tion of the tetrahydropyran core. A highly functionalized
side-chain was constructed by means of a Sharpless asym-
metric dihydroxylation and Evan’s alkylation reaction. Cou-
pling of both key fragments was achieved by olefin cross-
metathesis. This approach can be applied for the synthesis
of other congeners of the GEX family.
3
max
1438, 1378, 1052, 969, 651 cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 5.33–5.61 (m, 2 H), 3.73–3.87 (m, 3 H), 2.57 (br. s, 2 H),
2.07–2.22 (m, 2 H), 1.61–1.73 (m, 5 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 129.0, 126.6, 71.2, 61.4, 41.0, 37.7, 18.0 ppm.
HRMS (+ESI): calcd. for C7H14O2Na [M + Na]+ 153.0886; found
153.0884.
(E)-3-[(2R,3R,4R,6R)-6-(2-Hydroxyethyl)-4-iodo-3-methyl-tetra-
hydro-2H-pyran-2-yl]but-2-enyl Pivalate (13): To a mixture of
homoallylic alcohol 4 (1.250 g, 9.6 mmol) and aldehyde 5 (2.120 g,
11.5 mmol) in dichloroethane (30 mL) was added CeCl3·7H2O
(3.552 g, 9.6 mmol) and LiI (1.930 g, 14.4 mmol) and the reaction
mixture was heated to reflux at 80 °C for 5 h. After completion of
the reaction, the reaction mixture was diluted with water (20 mL)
and extracted with dichloromethane (2ϫ 30 mL). The combined
organic layers were dried with anhydrous Na2SO4, concentrated in
vacuo, and the crude product was purified by silica gel column
chromatography (15% EtOAc/hexanes) to afford 4-iodotetrahydro-
pyran 13 (3.098 g, 76% yield) as a pale yellow oil. [α]2D0 = –73.7 (c
Experimental Section
General Methods: Air- and/or moisture-sensitive reactions were car-
ried out in anhydrous solvents under an argon atmosphere in oven-
or flame-dried glassware. All anhydrous solvents were distilled
prior to use: THF and diethyl ether over Na/benzophenone;
CH2Cl2 and nitriles over CaH2; MeOH over Mg cake. Commercial
reagents were used as received. Column chromatography was car-
ried out with silica gel (Merck 60–120 mesh and 100–200 mesh),
and technical-grade hexane and ethyl acetate were distilled and
used as the mobile phase. Specific optical rotations [α]D are given
in 10–1 degcm2 g–1. Infrared spectra were recorded by using KBr
optics/neat (as mentioned). 1H and 13C NMR spectra were re-
corded with an internal deuterium lock on Bruker 300 MHz, Var-
= 1.0, CHCl ). IR (neat): ν
= 3447, 2965, 2872, 1725, 1478,
˜
3
max
1456, 1371, 1281, 1149, 1092, 1058, 1029, 978, 771, 548 cm–1. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 5.52 (t, J = 6.8 Hz, 1 H),
4.50–4.68 (m, 2 H), 3.97–4.05 (m, 1 H), 3.74 (t, J = 5.3 Hz, 2 H),
3.56–3.65 (m, 1 H), 3.45 (d, J = 9.8 Hz, 1 H), 2.38–2.46 (m, 2 H),
2.25 (q, J = 12.8 Hz, 1 H), 1.82–1.94 (m, 1 H), 1.64–1.79 (m, 1 H),
1.68 (s, 3 H), 1.18 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 178.3, 138.9, 124.0, 88.4, 78.4,
60.6, 60.3, 46.5, 42.6, 38.7, 37.1, 35.5, 27.1, 19.1, 11.8 ppm. HRMS
(+ESI): calcd. for C17H29O4INa [M + Na]+ 447.1002; found
447.1003.
ian 400 MHz and Inova 500 MHz spectrophotometers. 1H and 13
C
NMR chemical shifts are reported relative to tetramethylsilane. The
following abbreviations are used to designate signal multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet,
m = multiplet, br. = broad.
Experimental Procedures
(E)-3-[(2R,3S,6S)-6-(2-Hydroxyethyl)-3-methyl-tetrahydro-2H-
pyran-2-yl]but-2-enyl Pivalate (14): To a solution of 13 (2.550,
6.0 mmol) in dimethyl sulfoxide (25 mL) at 0 °C was added NaBH4
(0.685 g, 18 mmol) portion-wise and the reaction mixture was grad-
ually heated to 85 °C over a period of 1 h. After completion of the
reaction, the mixture was cooled to 0 °C, diluted with diethyl ether
(100 mL) and quenched with ice-cold water (100 mL). The layers
were separated and the aqueous phase was extracted with diethyl
ether (3ϫ 50 mL) and combined organic layers were dried with
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
product was then purified by silica gel column chromatography
(15% EtOAc/hexanes) to afford tetrahydropyran 14 as a colorless
oil (1.613 g, 90% yield). [α]2D0 = –3.0 (c = 1.0, CHCl3). IR (neat):
(3R,5E)-1-(Benzyloxy)hept-5-en-3-ol (12): p-TSA·H2O (455 mg,
2.39 mmol) was added to a solution of 3-benzyloxypropanal
(4.020 g, 24.48 mmol) and (–)-(1R,2S,4R,1ЈR)-1-(1-methylallyl)-
menthol (11; 10.060 g, 47.82 mmol) in dry CH2Cl2 (250 mL) at
room temperature. The mixture was stirred for 22 h and then trieth-
ylamine (1 mL) and saturated aqueous sodium hydrogen carbonate
solution (250 mL) were added and the mixture was stirred vigor-
ously for 15 min. The layers were separated and the aqueous phase
was extracted with CH2Cl2 (3ϫ 150 mL). The combined organic
extracts were washed with saturated aqueous sodium hydrogen
carbonate solution (200 mL) and brine (200 mL), dried with
Na2SO4, filtered, and concentrated in vacuo to give a yellow oil
(15.64 g) that was purified by column chromatography (5% EtOAc/
hexanes) on silica gel to give homoallylic alcohol 12 as a yellow oil
ν
max = 3442, 2957, 2928, 2873, 1728, 1479, 1457, 1372, 1283, 1154,
˜
1
1069, 1032, 956, 771 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ
= 5.50 (t, J = 6.6 Hz, 1 H), 4.51–4.67 (m, 2 H), 3.75 (t, J = 5.1 Hz,
2 H), 3.55–3.62 (m, 1 H), 3.35 (d, J = 9.8 Hz, 1 H), 1.80–1.86 (m,
1 H), 1.69–1.77 (m, 2 H), 1.67 (s, 3 H), 1.35–1.60 (m, 3 H), 1.19–
1.26 (m, 1 H), 1.17 (s, 9 H), 0.68 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 178.4, 139.6, 122.9, 89.8,
78.7, 61.8, 60.5, 38.7, 37.7, 32.2, 32.1, 31.8, 27.1, 17.5, 11.9 ppm.
HRMS (+ESI): calcd. for C17H30O4Na [M + Na]+ 321.2036; found
321.2035.
(4.658 g, 86%). [α]2D5 = –4.2 (c = 0.4, CHCl ). IR (neat): ν
=
˜
3
max
3421, 3063, 3028, 2919, 2828, 1718, 1492, 1450, 1363, 1276, 1207,
1097, 1025, 969, 739, 698 cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.20–7.37 (m, 5 H), 5.35–5.55 (m, 2 H), 4.50 (s, 2 H),
3.56–3.81 (m, 3 H), 2.60 (br. s, 1 H), 2.13 (t, J = 6.0 Hz, 2 H),
1.69–1.75 (m, 2 H), 1.68 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 138.5, 128.8, 128.7, 128.1, 128.0,
127.6, 73.7, 70.9, 69.3, 41.1, 36.3, 18.4 ppm. MS (ESI): m/z = 221
[M + H]+.
(3R,5E)-Hept-5-ene-1,3-diol (4): To a solution of sodium (2.00 g,
86.9 mmol) in liquid NH3 (60 mL) was added compound 12
(2.376 g, 10.8 mmol) in dry THF (10 mL). The mixture was stirred
for 3 min and quenched with solid NH4Cl (4.650 g). NH3 was al-
lowed to evaporate and the residual mixture was taken in ethyl
acetate (50 mL), and washed with water (20 mL), brine (20 mL),
and dried with anhydrous Na2SO4. Evaporation of the solvent and
chromatography (30% EtOAc/hexanes) of the crude product af-
forded pure diol 4 (1.376 g, 98% yield) as a pale yellow liquid.
2-{(2S,5S,6R)-5-Methyl-6-[(E)-4-(pivaloyloxy)but-2-en-2-yl]-tetra-
hydro-2H-pyran-2-yl}acetic Acid (15): Bis(acetoxy)iodobenzene
(2.350 g, 7.3 mmol) and TEMPO (0.156 g, 1.0 mmol) were added
sequentially to the stirred solution of alcohol 14 (1.460 g,
4.9 mmol) in CH2Cl2 (50 mL) and water (25 mL) at 0 °C and
warmed to room temperature. After completion of the reaction,
saturated aqueous Na2S2O3 (50 mL) and Et2O (100 mL) were
added. The separated organic phase was washed with saturated
aqueous NaHCO3 and brine, dried with anhydrous Na2SO4, fil-
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A Formal Synthesis of Herboxidiene/GEX1A
tered, and concentrated under reduced pressure to obtain the crude
product, which was purified by silica gel column chromatography
(40% EtOAc/hexanes) to afford pure acid 15 (1.253 g, 82% yield)
A saturated solution of NaHCO3 (10 mL) and Na2S2O3 (10 mL,
1 m) was added to the mixture and stirred vigorously until the or-
ganic layer turned clear. The organic layer was separated and the
aqueous layer was extracted with EtOAc (3ϫ 10 mL). The com-
bined organic layers were washed with brine (10 mL), dried with
Na2SO4, and concentrated in vacuo to obtain the crude aldehyde
(0.185 g, 85% yield), which was directly subjected to Wittig ole-
fination. To a suspension of Ph3PCH3Br (1.372 g, 3.8 mmol) in
THF (5.0 mL) at 0 °C, was added nBuLi (1.4 mL, 2.5 m in THF,
as a colorless liquid. [α]2D0 = –2.1 (c = 1.0, CHCl ). IR (neat): ν
˜
3
max
= 3446, 2957, 2924, 2851, 1730, 1715, 1459, 1377, 1283, 1154, 1071,
1031, 970, 771 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 5.56
(t, J = 6.7 Hz, 1 H), 4.54–4.71 (m, 2 H), 3.75–3.84 (m, 1 H), 3.46
(d, J = 10.5 Hz, 1 H), 2.59 (d, J = 1.5 Hz, 1 H), 2.57 (s, 1 H), 1.85–
1.94 (m, 1 H), 1.71 (s, 3 H), 1.66–1.75 (m, 2 H), 1.51–1.65 (m, 2
H), 1.19 (s, 9 H), 0.73 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR 3.4 mmol) dropwise through a syringe. The resulting solution was
(100 MHz, CDCl3, 25 °C): δ = 178.3, 174.7, 139.1, 123.5, 90.4, 73.6,
60.6, 40.9, 38.7, 31.9, 31.8, 31.4, 29.7, 27.1, 17.4, 11.9 ppm. HRMS
(+ESI): calcd. for C17H28O5Na [M + Na]+ 335.1829; found
335.1822.
warmed to room temperature and then cooled to –78 °C over a
period of 30 min. To this solution was slowly added aldehyde
(0.185 g, 0.77 mmol) in THF (3 mL) through a cannula and the
reaction mixture was warmed to room temperature and stirred for
1 h. Then the reaction was quenched with saturated NH4Cl solu-
tion (10 mL), the organic layer was separated and the aqueous layer
was extracted with EtOAc (2ϫ 10 mL). The combined organic lay-
ers were washed with brine (10 mL), dried with Na2SO4 and con-
centrated in vacuo. The crude product was purified by column
chromatography (3% EtOAc/hexanes) to afford olefin 2 (0.137 g,
75% yield) as a colorless semi-solid. [α]2D0 = +50.8 (c = 0.25,
(E)-3-[(2R,3S,6S)-6-(2-Methoxy-2-oxoethyl)-3-methyl-tetrahydro-
2H-pyran-2-yl]but-2-enyl Pivalate (16): An ice-cold solution of 50%
aqueous KOH (5 mL) and diethyl ether (10 mL) were taken in a
separating funnel and to this was slowly added N-nitroso-N-meth-
ylurea (1.143 g, 11.1 mmol) with careful shaking (without placing
the stopper). Then the organic layer was separated, dried with an-
hydrous KOH pellets and transferred into a solution of 15 (1.155 g,
3.7 mmol) in diethyl ether at 0 °C with slow stirring. Then the sol-
vent was removed under vacuum and the crude product was puri-
fied by silica gel column chromatography (10% EtOAc/hexanes) to
furnish pure ester 16 (1.182 g, 98 % yield) as a colorless liquid.
CHCl ). IR (Neat): ν
= 2953, 2926, 2852, 1742, 1651, 1601,
˜
3
max
1437, 1380, 1340, 1293, 1253, 1198, 1160, 1068, 1020, 990, 902,
764, 662 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 6.58 (dt, J
= 10.6, 16.6 Hz, 1 H), 5.97 (d, J = 10.6 Hz, 1 H), 5.05–5.21 (m, 2
H), 3.72–3.82 (m, 1 H), 3.66 (s, 3 H), 3.35 (d, J = 9.8 Hz, 1 H),
2.60 (dd, J = 9.0, 6.0 Hz, 1 H), 2.40 (dd, J = 8.3, 6.8 Hz, 1 H),
1.80–1.88 (m, 1 H), 1.73 (d, J = 1.5 Hz, 3 H), 1.46–1.71 (m, 2
H), 1.15–1.41 (m, 2 H), 0.70 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 171.8, 137.3, 132.7, 128.6, 116.9,
90.2, 73.8, 51.5, 41.3, 32.3, 32.2, 31.6, 17.6, 12.2 ppm. HRMS
(+ESI): calcd. for C14H22O3Na [M + Na]+ 261.1461; found
261.1455.
[α]2D0 = +5.6 (c = 1.0, CHCl ). IR (neat): ν
= 2956, 2924, 2853,
˜
3
max
1734, 1459, 1374, 1282, 1154, 1071, 1052, 771 cm–1 1H NMR
.
(400 MHz, CDCl3, 25 °C): δ = 5.50 (t, J = 6.8 Hz, 1 H), 4.54–4.68
(m, 2 H), 3.74–3.81 (m, 1 H), 3.66 (s, 3 H), 3.35 (d, J = 9.8 Hz, 1
H), 2.38–2.63 (m, 2 H), 1.81–1.88 (m, 1 H), 1.69–1.72 (m, 1 H),
1.68 (s, 3 H), 1.45–1.57 (m, 1 H), 1.22–1.40 (m, 2 H), 1.18 (s, 9 H),
0.69 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 178.4, 171.8, 139.6, 122.7, 89.8, 73.8, 60.7, 51.6, 41.2,
38.7, 32.2, 32.0, 31.6, 27.2, 17.5, 12.0 ppm. HRMS (+ESI): calcd.
for C18H30O5Na [M + Na]+ 349.1985; found 349.1982.
(S)-Methyl 3-(Benzyloxy)-2-methylpropanoate (18): Benzyl 2,2,2-
trichloroacetimidate (2.23 mL, 12.0 mmol, 1.2 equiv.) was added
dropwise to a stirred solution of methyl (S)-3-hydroxy-2-methyl-
propionate (1.11 mL, 10.0 mmol) in cyclohexane/dichloromethane
(2:1, 15 mL) at 0 °C. Trifluoromethanesulfonic acid (53 μL,
1 mmol, 0.1 equiv.) was then added dropwise and the reaction mix-
ture was slowly warmed to room temp. After stirring for 1 h, the
reaction mixture was filtered and washed with dichloromethane
(2ϫ 15 mL). The filtrate was then sequentially washed with satu-
rated aqueous sodium hydrogen carbonate solution (20 mL) and
brine solution (20 mL), dried with Na2SO4, filtered, and concen-
trated in vacuo. The crude product was purified by flash column
chromatography (3% EtOAc/hexanes) to afford 18 (1.91 g, 92%
Methyl 2-{(2S,5S,6R)-6-[(E)-4-Hydroxybut-2-en-2-yl]-5-methyl-
tetrahydro-2H-pyran-2-yl}acetate (17): To a solution of pivalate es-
ter 16 (0.456 g, 1.4 mmol) in methanol (10 mL) was added potas-
sium carbonate (0.966 g, 7.0 mmol) at 0 °C and warmed to room
temperature over a period of 3 h. Methanol was then removed un-
der reduced pressure and water (10 mL) was added. The mixture
was extracted with dichloromethane (3ϫ 20 mL) and the combined
organic layers were dried with Na2SO4 and the solvent was re-
moved under reduced pressure. Column chromatography (20 %
EtOAc/hexanes) of the crude mixture afforded pure alcohol 17
(0.298 g, 88% yield) as a colorless oil. [α]2D0 = +19.2 (c = 0.25,
yield) as a clear oil. [α]2D0 = +12.0 (c = 1.0, CHCl ). IR (neat): ν
˜
3
max
CHCl ). IR (neat): νmax = 3425, 2925, 2853, 1738, 1637, 1439, 1377,
˜
3
= 3030, 2979, 2943, 2861, 1737, 1516, 1455, 1365, 1250, 1199, 1096,
1027, 824, 740, 698 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.25–7.39 (m, 5 H), 4.47–4.59 (m, 2 H), 3.70 (s, 3 H), 3.64–3.70 (m,
1 H), 3.48–3.52 (m, 1 H), 2.75–2.84 (m, 1 H), 1.19 (d, J = 7.1 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 175.3, 138.0,
129.0, 128.2, 127.4, 73.1, 71.8, 51.5, 40.1, 13.9 ppm. MS (ESI): m/z
= 231 [M + Na]+.
1343, 1286, 1200, 1157, 1068, 1014, 766, 542 cm–1 1H NMR
.
(400 MHz, CDCl3, 25 °C): δ = 5.58 (t, J = 6.4 Hz, 1 H), 4.21 (t, J
= 6.4 Hz, 1 H), 3.73–3.82 (m,1 H), 3.67 (s, 3 H), 3.35 (d, J = 9.8 Hz,
1 H), 2.37–2.64 (m,2 H), 1.81–1.88 (m, 1 H), 1.47–1.73 (m, 2 H),
1.65 (s, 3 H), 1.16–1.43 (m, 2 H), 0.72 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.7, 137.2, 127.5, 90.0,
74.0, 59.0, 51.5, 41.2, 32.2, 32.0, 31.6, 17.8, 11.9 ppm. HRMS
(+ESI): calcd. for C13H22O4Na [M + Na]+ 265.1410; found
265.1408.
(R,E)-Ethyl 5-(Benzyloxy)-4-methylpent-2-enoate (9): DIBAL-H
(7.9 mL, 12.7 mmol, 1.6 m solution in toluene) was added dropwise
to a solution of ester 18 (2.205 g, 10.6 mmol) in CH2Cl2 (35 mL) at
Methyl 2-{(2S,5S,6R)-5-Methyl-6-[(E)-penta-2,4-dien-2-yl]tetra- –78 °C and stirred for 15 min at the same temperature. The reaction
hydro-2H-pyran-2-yl}acetate (2): To a solution of Dess–Martin
Periodinane (0.579 g, 1.4 mmol) in CH2Cl2 (10 mL) was added
H2O (30 μL). To the resulting cloudy suspension was added a solu-
tion of the alcohol 17 (0.220 g, 0.91 mmol) in CH2Cl2 (5 mL). The
mixture was stirred until the starting material disappeared (≈ 0.5 h).
mixture was then quenched by adding saturated aqueous sodium
potassium tartrate solution (20 mL) followed by vigorous stirring
for 1 h. The aqueous phase was then extracted with CH2Cl2 (3ϫ
30 mL) and the combined organic layers were washed with brine
(10 mL), dried with Na2SO4 and the solvent removed in vacuo. The
Eur. J. Org. Chem. 2014, 4389–4397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4393

J. S. Yadav, G. M. Reddy, S. R. Anjum, B. V. S. Reddy
FULL PAPER
crude aldehyde (1.604 g, 9.0 mmol) thus obtained was dissolved in
benzene (30 mL), Ph3PCHCOOEt (3.758 g, 9.9 mmol) was added
and the reaction mixture was heated to reflux at 80 °C for 1 h.
Then the reaction was quenched by adding H2O (15 mL), and the
aqueous phase was extracted with EtOAc (3ϫ 20 mL). The com-
bined organic layers were dried with Na2SO4, solvent removed in
vacuo, and the residue was purified by SiO2 gel flash chromatog-
raphy (3% EtOAc/hexanes) to give 9 (2.056 g, 92% yield) as a col-
{(4R,5R)-5-[(S)-1-(Benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}methanol (21): To a solution of ester 20 (4.250 g,
13.20 mmol) in dry CH2Cl2 (70 mL) was added DIBAL-H
(20.6 mL, 33.0 mmol, 1.6 m solution in toluene) dropwise at 0 °C.
After warming the reaction mixture to r.t over a period of 1 h, the
reaction was quenched with saturated aqueous solution of sodium
potassium tartarate (50 mL) and the aqueous layer was extracted
with CH2Cl2 (3 ϫ 35 mL). The combined organic layers were
washed with brine, dried with anhydrous Na2SO4, filtered, and con-
centrated in vacuo. The crude product was purified by column
chromatography (15 % EtOAc/hexanes) to afford alcohol 21
orless oil. [α]2D0 = +13.2 (c = 1.0, CHCl ). IR (neat): ν
= 2978,
˜
3
max
2873, 1718, 1653, 1454, 1368, 1307, 1271, 1187, 1155, 1096, 1033,
985, 743, 699 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.22–
7.31 (m, 5 H), 6.89 (dd, J = 15.5, 7.3 Hz, 1 H), 5.81 (d, J = 15.5 Hz, (3.030 g, 82% yield) as colorless oil. [α]2D5 = +19.1 (c = 2.0, CHCl3).
1 H), 4.49 (s, 2 H), 4.17 (q, J = 7.3 Hz, 2 H), 3.32–3.41 (m, 2 H),
2.63 (quint, J = 7.3 Hz, 1 H), 1.29 (t, J = 7.3 Hz, 3 H), 1.11 (d, J
IR (neat): ν
= 3451, 2985, 2932, 2875, 1636, 1456, 1374, 1247,
˜
max
1216, 1168, 1103, 1053, 902, 854, 743, 699, 611, 512 cm–1. 1H NMR
= 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = (400 MHz, CDCl3, 25 °C): δ = 7.27–7.38 (m, 5 H), 4.50 (s, 2 H),
166.5, 151.0, 138.1, 128.3, 128.2, 127.5, 127.5, 120.9, 73.8, 72.9,
60.1, 36.7, 15.9, 14.2 ppm. HRMS (+ESI): calcd. for C15H21O3 [M
+ H]+ 249.1489; found 249.1490.
3.98–4.03 (m, 1 H), 3.91 (dd, J = 6.3, 8.3 Hz, 1 H), 3.73–3.79 (m,
1 H), 3.58–3.65 (m, 1 H), 3.43 (d, J = 6.3 Hz, 2 H), 1.93–2.06 (m,
1 H), 1.41 (s, 3 H), 1.40 (s, 3 H), 1.04 (d, J = 6.3 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 138.3, 128.4, 127.7, 127.6,
108.5, 79.2, 78.5, 73.1, 73.0, 62.8, 36.1, 27.1, 12.6 ppm. HRMS
(+ESI): calcd. for C16H24O4Na [M + Na]+ 303.1566; found
303.1567.
(2S,3R,4S)-Ethyl 5-(Benzyloxy)-2,3-dihydroxy-4-methylpentanoate
(19): A mixture of unsaturated ester 9 (5.704 g, 23.0 mmol), tBuOH
(45 mL), H2O (45 mL), methanesulfonamide (2.628 g, 27.6 mmol),
and enriched AD-mix-β [35 g, K3Fe(CN)6, 23.85 g; K2CO3,
10.02 g; (DHQD)2PHAL, 0.94 g, K2OsO2(OH)4, 185 mg] was
stirred at 0 °C for 6 h. EtOAc (200 mL) and anhydrous Na2SO3
(28 g) were added, and the mixture was stirred at 20 °C for 45 min.
The precipitate was filtered off and the solution diluted with H2O
(100 mL) and extracted with EtOAc. The combined organic ex-
tracts were washed with aqueous HCl (1 m) and with brine, and
dried with Na2SO4. Removal of solvent in vacuo afforded the crude
diol, which was purified by silica gel column chromatography (50%
EtOAc/hexanes) to furnish an inseparable 93:7 diastereomeric mix-
{(4R,5R)-5-[(S)-1-(Benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}methyl-4-methylbenzenesulfonate (22): To a stirred solu-
tion of alcohol 21 (2.950 g, 10.53 mmol), triethylamine (2.2 mL,
15.80 mmol) and DMAP (catalytic) in dry dichloromethane
(50 mL) at 0 °C was added p-toluene sulfonyl chloride (2.403 g,
12.64 mmol) portion wise. After stirring for 1 h at r.t, the resulting
mixture was quenched with saturated aqueous NaHCO3 solution.
The organic layer was extracted with dichloromethane (2ϫ 20 mL),
washed with brine and dried with anhydrous Na2SO4. Removal of
the solvent under reduced pressure and purification by silica gel
chromatography (10% EtOAc/hexanes) afforded 22 (4.115 g, 90%)
1
ture (identified from H NMR spectrum) of 19 as pale yellow oil
(5.707 g, quantities to obtain the analytical data of the pure dia-
as a viscous liquid. [α]2D5 = +25.8 (c = 2.0, CHCl ). IR (neat): ν
˜
3
max
stereomer). [α]2D5 = +4.9 (c = 2.0, CHCl ). IR (neat): ν
= 3424,
˜
3
max
= 2986, 2934, 2873, 1598, 1454, 1365, 1251, 1215, 1179, 1097, 1057,
2978, 2934, 1735, 1639, 1454, 1369, 1271, 1211, 1139, 1096, 1047,
862, 741, 700 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.27–
7.38 (m, 5 H), 4.52 (dd, J = 12.2, 14.7 Hz, 2 H), 4.23–4.31 (m, 3
H), 3.90 (dd, J = 6.4,2.2 Hz, 1 H), 3.49–3.57 (m, 2 H), 3.39 (br. s,
1 H), 2.07–2.17 (m, 1 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.06 (d, J =
7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 173.5,
137.8, 128.3, 127.7, 127.6, 74.7, 73.2, 73.0, 71.7, 61.8, 36.8, 14.1,
13.2 ppm. HRMS (+ESI): calcd. for C15H22O5Na [M + Na]+
305.1359; found 305.1357.
981, 912, 820, 772, 699, 665, 554 cm–1 1H NMR (500 MHz,
.
CDCl3, 25 °C): δ = 7.77 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz,
2 H), 7.28–7.36 (m, 5 H), 4.45 (s, 2 H), 4.05–4.16 (m, 3 H), 3.84 (t,
J = 6.5 Hz, 1 H), 3.34–3.40 (m, 2 H), 2.43 (s, 3 H), 1.91–1.97 (m,
1 H), 1.34 (s, 3 H), 1.30 (s, 3 H), 0.98 (d, J = 6.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 144.8, 138.1, 132.7, 129.8,
128.3, 128.0, 127.6, 127.5, 109.1, 78.9, 76.4, 73.0, 69.9, 36.2, 36.2,
27.0, 26.7, 21.6, 12.6 ppm. HRMS (+ESI): calcd. for C23H30O6NaS
[M + Na]+ 457.1655; found 457.1660.
(4S,5R)-Ethyl-5-[(S)-1-(benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-di-
(2R,3R,4S)-5-(Benzyloxy)-2,3-dihydroxy-4-methylpentyl-4-methyl-
oxolane-4-carboxylate (20): To a stirred solution of 19 (5.550 g, benzenesulfonate (23): To a stirred solution of compound 22
19.68 mmol) in acetone (40 mL) was added 2,2-dimethoxy propane
(7.25 mL, 59.06 mmol) and p-TSA (145 mg). The mixture was
stirred at ambient temperature for 12 h. The reaction mixture was
then quenched with solid sodium hydrogen carbonate and filtered.
Solvent was evaporated under vacuum to obtain a mixture of dia-
stereomers, which were separated by silica gel chromatography
(10 % EtOAc/hexanes) to obtain pure diastereomer 20 (5.386 g,
85% yield) as a colorless liquid. [α]2D0 = +25.0 (c = 1.0, CHCl3). IR
(4.050 g, 9.3 mmol) in methanol (30 mL) was added p-TSA
(0.160 g, 0.93 mmol) and the reaction mixture was stirred for 12 h
at room temperature. Sodium hydrogen carbonate was added to the
reaction mixture to neutralize p-TSA and filtered. The filtrate was
concentrated under reduced pressure and the crude product was
purified by silica gel column chromatography (40 % EtOAc/hex-
anes) to afford diol 23 (3.125 g, 85%) as a white solid. [α]2D0 = +1.1
(c = 2.0, CHCl ), m.p. 60–62 °C. IR (KBr): ν
= 3423, 3324,
˜
3
max
(neat): νmax = 2986, 2932, 1746, 1633, 1456, 1375, 1261, 1203, 1101,
3064, 3035, 2966, 2921, 2859, 2801, 1729, 1600, 1455, 1419, 1353,
˜
1
868, 811, 742, 698 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ =
1267, 1185, 1148, 1095, 1058, 984, 961, 914, 891, 833, 813, 748,
7.27–7.37 (m, 5 H), 4.48 (s, 2 H), 4.36 (d, J = 7.3 Hz, 1 H), 4.12– 699, 663, 581, 554, 516 cm–1. H NMR (300 MHz, CDCl3, 25 °C):
1
4.31 (m, 3 H), 3.41–3.48 (m, 2 H), 2.10–2.19 (m, 1 H), 1.44 (d, J δ = 7.79 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.3 Hz, 2 H), 7.27–7.39
= 9.5 Hz, 6 H)1.24 (t, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3
(m, 5 H), 4.49 (s, 2 H), 4.00–4.10 (m, 2 H), 3.87–3.93 (m, 1 H),
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.1, 138.3, 3.57 (dd, J = 3.0, 5.3 Hz, 1 H), 3.53 (d, J = 3.7 Hz, 1 H), 3.57 (dd,
128.3, 127.5, 127.4, 127.3, 110.4, 80.1, 77.1, 72.9, 72.7, 61.3, 36.1,
26.9, 25.6, 14.0, 11.9 ppm. HRMS (+ESI): calcd. for C20H25O5Na
[M + Na]+ 345.1701; found 345.1699.
J = 6.8, 9.8 Hz, 1 H), 2.44 (s, 3 H), 1.90–1.99 (m, 1 H), 0.99 (d, J
= 7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
144.5, 137.4, 132.5, 129.8, 128.4, 127.9, 127.8, 127.7, 73.4, 72.8,
4394
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4389–4397

A Formal Synthesis of Herboxidiene/GEX1A
72.7, 70.9, 69.1, 36.8, 21.5, 12.6 ppm. HRMS (+ESI): calcd. for
C20H26O6NaS [M + Na]+ 417.1366; found 417.1347.
[(2R,3R,4S)-5-(Benzyloxy)-3-methoxy-4-methylpentan-2-yloxy]-
(tert-butyl)dimethylsilane (27): To an ice-cooled solution of alcohol
26 (2.310 g, 9.7 mmol) and imidazole (1.448 g, 21.3 mmol) in dry
dichloromethane (40 mL) was added TBSCl (1.605 g, 10.7 mmol).
After stirring for 15 min at 0 °C the reaction mixture was warmed
to room temperature and stirred for another 6 h. Then the reaction
mixture was quenched with saturated aqueous NH4Cl solution and
extracted with dichloromethane (2ϫ 30 mL). The combined ex-
tracts was washed with brine, dried with anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography (3% EtOAc/hexanes) to afford silyl ether 27
(3.075 g, 90% yield) as a viscous liquid. [α]2D0 = +11.0 (c = 1.0,
(1R,2S)-3-(Benzyloxy)-2-methyl-1-[(R)-oxiran-2-yl]propan-1-ol (24):
To a solution of diol 23 (3.075 g, 7.8 mmol) in methanol (30 mL)
was added potassium carbonate (1.30 g, 9.4 mmol) at 0 °C and
warmed to room temperature over a period of 1 h. Methanol was
then removed under reduced pressure and water (15 mL) was
added. The mixture was extracted with dichloromethane (3 ϫ
20 mL) and the combined organic layers were dried with Na2SO4
and the solvent was removed under reduced pressure. Column
chromatography (20% EtOAc/hexanes) of the crude mixture af-
forded epoxy alcohol 24 (1.49 g, 86%) as a colorless oil. [α]2D5
–12.0 (c = 1.0, CHCl ). IR (neat): ν = 3449, 3031, 2969, 2867,
=
CHCl ). IR (neat): νmax = 3031, 2956, 2931, 2888, 2857, 1633, 1458,
˜
3
˜
3
max
1380, 1254, 1158, 1098, 989, 927, 834, 775, 751, 698 cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.27–7.37 (m, 5 H), 4.50 (s, 2 H),
3.85 (quint, J = 6.6 Hz, 1 H), 3.46–3.52 (m, 1 H), 3.43 (s, 3 H),
3.30 (dd, J = 6.2, 8.8 Hz, 1 H), 3.10 (dd, J = 3.9, 7.1 Hz, 1 H),1.94–
2.06 (m, 1 H), 1.09 (d, J = 6.4 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H),
0.89 (s, 9 H), 0.07 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 138.5, 128.3, 127.6, 127.4, 85.5, 73.2, 72.9, 70.4, 60.9,
34.8, 25.9, 20.1, 18.0, 10.9, –4.7 ppm. HRMS (+ESI): calcd. for
C20H36O3Na Si [M + Na]+ 375.2331; found 375.2324.
1637, 1455, 1367, 1256, 1210, 1098, 991, 914, 869, 742, 698 cm–1.
1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.25–7.39 (m, 5 H), 4.52
(q, J = 12.1 Hz, 2 H), 3.62–3.67 (m, 1 H), 3.57 (t, J = 8.4 Hz, 1
H), 3.50 (q, J = 4.6 Hz, 1 H), 3.07 (q, J = 3.7 Hz, 1 H), 2.75 (t, J
= 4.6 Hz, 1 H), 2.71 (q, J = 2.8 Hz, 1 H), 2.47 (d, J = 7.4 Hz, 1
H), 2.03–2.16 (m, 1 H), 1.03 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 138.0, 128.3, 127.6, 73.3, 73.1, 72.3,
53.5, 44.0, 37.8, 11.9 ppm. HRMS (+ESI): calcd. for C13H18O3Na
[M + Na]+ 245.1148; found 245.1152.
(2S,3R,4R)-4-(tert-Butyldimethylsilyloxy)-3-methoxy-2-methyl-
pentan-1-ol (8): To a solution of benzyl ether 27 (2.950 g, 8.4 mmol)
in ethyl acetate (15 mL), under an atmosphere of nitrogen, was
added palladium on activated carbon (10%, 90 mg). The flask was
flushed with nitrogen followed by hydrogen, and the solution was
stirred under a hydrogen atmosphere for 2 h. The reaction mixture
was diluted with diethyl ether (60 mL), filtered through a pad of
Celite and concentrated in vacuo to yield alcohol 8 (2.086 g, 95%
yield) as a colorless oil. [α]2D0 = +12.4 (c = 0.50, CHCl3). IR (neat):
(R)-2-[(1R,2S)-3-(Benzyloxy)-1-methoxy-2-methylpropyl]oxirane
(25): To a cooled (–15 °C) solution of epoxy alcohol 24 (2.980 g,
13.4 mmol) and MeI (8.3 mL, 134 mmol) in anhydrous THF
(130 mL) was added portion-wise, NaH (60% dispersion in mineral
oil; 0.804 g, 20.1 mmol) under nitrogen atmosphere and the reac-
tion mixture was stirred at 0 °C for 1 h. Water (50 mL) and Et20
(100 mL) were added, the organic phase was separated and the
aqueous layer extracted with Et2O (2ϫ 100 mL). The combined
organic phases were washed with brine (50 mL), dried with
Na2SO4, and concentrated in vacuo. Flash chromatography (10%
EtOAc/hexanes) of the residue on silica gel afforded epoxy ether
25 (2.788 g, 88%) as a colorless oil. [α]2D0 = +9.8 (c = 1.0, CHCl3).
ν
max = 3444, 2956, 2931, 2858, 1638, 1467, 1381, 1254, 1157, 1096,
˜
1034, 988, 928, 835, 776, 667 cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 4.02 (quint, J = 6.6 Hz, 1 H), 3.59 (dd, J = 3.7, 11.5 Hz,
1 H), 3.49 (dd, J = 7.1, 11.5 Hz, 1 H), 3.43 (s, 3 H), 2.89 (dd, J =
5.1, 7.7 Hz, 1 H), 1.84–1.93 (m, 1 H), 1.18 (d, J = 6.2 Hz, 3 H),
0.91 (s, 9 H), 0.89 (d, J = 3.4 Hz, 3 H), 0.13 (s, 3 H), 0.12 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 88.1, 69.2, 66.4,
59.9, 36.8, 25.7, 18.3, 17.9, 13.1, –4.8, –4.9 ppm. HRMS (+ESI):
calcd. for C13H30O3NaSi [M + Na]+ 285.1861; found 285.1869.
IR (neat): ν
= 3031, 2974, 2932, 1628, 1456, 1365, 1258, 1199,
˜
max
1092, 949, 950, 871, 840, 741, 699 cm–1 1H NMR (400 MHz,
.
CDCl3, 25 °C): δ = 7.26–7.37 (m, 5 H), 4.49 (s, 2 H), 3.44–3.49 (m,
1 H), 3.47 (s, 3 H), 3.36–3.41 (m, 1 H), 3.02–3.06 (m, 1 H), 2.92–
2.96 (m, 1 H), 2.73 (t, J = 4.8 Hz, 1 H), 2.48 (dd, J = 2.7, 5.0 Hz,
1 H), 1.97–2.06 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 138.3, 128.2, 127.5, 127.4, 82.8, 73.0,
72.0, 58.4, 53.7, 42.7, 37.1, 12.2 ppm. HRMS (+ESI): calcd. for
C14H20O3Na [M + Na]+ 259.1305; found 259.1310.
(4S,5R,6R,E)-Ethyl 6-(tert-Butyldimethylsilyloxy)-5-methoxy-2,4-
dimethylhept-2-enoate (28): IBX (2.490 mg, 8.9 mmol) was dis-
solved in DMSO/CH2Cl2 (1:1, 20 mL) at 0 °C. To this was added
a solution of alcohol 8 (1.950 g, 7.4 mmol) in CH2Cl2 (10 mL) at
the same temperature and stirred for 2 h at room temperature. Then
the reaction mixture was diluted with diethyl ether and filtered
(2R,3R,4S)-5-(Benzyloxy)-3-methoxy-4-methylpentan-2-ol (26): To
a suspension of LiAlH4 (0.640 g, 16.8 mmol) in THF (35 mL) at
0 °C was slowly added a solution of epoxide 25 (2.650 g,
11.2 mmol) in THF (20 mL) through a cannula and stirred for through a small pad of Celite. To this filtrate was added saturated
30 min. After completion of the reaction, the mixture was
quenched by slow addition of saturated aqueous NH4Cl (10 mL)
and the precipitate formed was filtered through a sintered funnel
and washed with EtOAc. The filtrate was concentrated under re-
duced pressure and the crude product was purified by silica gel
column chromatography (20% EtOAc/hexanes) to afford 26 as a
colorless oil (2.458 g, 92% yield). [α]2D0 = +6.8 (c = 2.0, CHCl3). IR
aqueous NaHCO3 solution and extracted with diethyl ether (2ϫ
30 mL). The combined organic extracts were dried with anhydrous
Na2SO4, filtered, and concentrated in vacuo to afford the corre-
sponding aldehyde (1.664 g, 86% yield) as a colorless oil. The crude
aldehyde thus obtained was dissolved in benzene (20 mL),
Ph3PCH(CH3)COOEt (3.485 g, 9.6 mmol) was added and the reac-
tion mixture was heated to reflux for 1 h. Then the reaction was
quenched by adding H2O (15 mL), and the aqueous phase was ex-
tracted with EtOAc (3ϫ 20 mL). The combined organic layers were
dried with Na2SO4, solvent removed in vacuo, and the residue was
(neat): νmax = 3450, 3063, 3030, 2972, 2932, 1637, 1455, 1368, 1256,
˜
1
1202, 1090, 950, 905, 744, 699 cm–1. H NMR (300 MHz, CDCl3,
25 °C): δ = 7.24–7.38 (m, 5 H), 4.46–4.56 (m, 2 H), 3.79 (quint, J
= 6.0 Hz, 1 H), 3.48 (s, 3 H), 3.44 (t, J = 6.0 Hz, 2 H), 3.07 (dd, J purified by silica gel flash chromatography (5% EtOAc/hexanes) to
= 3.7, 6.0 Hz, 1 H), 1.98–2.12 (m, 1 H), 1.19 (d, J = 6.0 Hz, 3 H),
afford ester 28 (1.805 g, 82% yield) as a colorless oil. [α]2D0 = –3.2
0.92 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): (c = 1.0, CHCl ). IR (neat): ν
= 2957, 2932, 2893, 2858, 1712,
˜
3
max
δ = 138.1, 128.3, 127.6, 127.5, 86.4, 73.0, 72.3, 67.8, 61.0, 35.2,
1648, 1465, 1369, 1250, 1147, 1096, 1002, 934, 834, 774, 667 cm–1.
19.4, 11.7 ppm. HRMS (+ESI): calcd. for C14H23O3 [M + H]+ 1H NMR (500 MHz, CDCl3, 25 °C): δ = 6.73 (d, J = 10.0 Hz, 1
239.1658; found 239.1647.
H), 4.13–4.22 (m, 2 H), 3.90 (quint, J = 5.0 Hz, 1 H), 3.44 (t, J =
4395
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. S. Yadav, G. M. Reddy, S. R. Anjum, B. V. S. Reddy
FULL PAPER
6.0 Hz, 3 H), 2.87 (t, J = 5.0 Hz, 1 H), 2.66–2.72 (m, 1 H), 1.84 (s,
3 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.10 (d, J = 6.0 Hz, 3 H), 1.02 (d,
J = 6.0 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 168.5, 145.2, 125.4, 88.4,
69.7, 69.1, 60.3, 34.6, 25.8, 19.3, 18.0, 15.1, 14.2, 12.4, –4.6,
–4.7 ppm. HRMS (+ESI): calcd. for C18H36O4NaSi [M + Na]+
367.2275; found 367.2278.
(2R,6S,7R,8R,E)-8-(tert-Butyldimethylsilyloxy)-7-methoxy-2,4,6-tri-
methylnon-4-en-1-ol (32): To a solution of 31 (0.805 g, 1.5 mmol)
in Et2O (5 mL) at 0 °C was added MeOH (80 μL, 1.8 mmol) and
LiBH4 (1.8 mL, 1.8 mmol, 1.0 m in THF). The solution was stirred
at r.t for 1 h and then quenched with NaOH (5.7 m, 1.1 mL) and
stirred vigorously at room temperature for 10 min. The organic
layer was separated and the aqueous layer was extracted with Et2O
(3ϫ 10 mL). The combined organic layers were dried with Na2SO4
and concentrated under vacuum. The crude product was purified
by silica gel column chromatography (10% EtOAc/hexanes) to give
alcohol 32 (0.428 g, 80% yield) as a colorless oil. [α]2D0 = +7.8 (c =
(4S,5R,6R,E)-6-(tert-Butyldimethylsilyloxy)-5-methoxy-2,4-dimeth-
ylhept-2-en-1-ol (7): To a solution of ester 28 (1.680 g, 4.9 mmol)
in dry CH2Cl2 (20 mL) was added DIBAL-H (7.6 mL, 12.2 mmol,
1.6 m solution in toluene) dropwise at 0 °C and stirred at the same
temperature for 1 h. Then the reaction was quenched with satu-
rated aqueous solution of potassium-sodium tartarate (20 mL) and
the aqueous layer was extracted with CH2Cl2 (3ϫ 25 mL). The
combined organic layers were washed with brine, dried with anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The crude prod-
uct was purified by column chromatography (25% EtOAc/hexanes)
0.5, CHCl ). IR (neat): ν
= 3479, 2931, 2858, 1750, 1463, 1379,
˜
3
max
1255, 1230, 1183, 1098, 1050, 991, 930, 873, 835, 779 cm–1 1H
.
NMR (400 MHz, CDCl3, 25 °C): δ = 5.20 (d, J = 8.3 Hz, 1 H),
3.84 (quint, J = 6.1 Hz, 1 H), 3.40–3.53 (m, 2 H), 3.45 (s, 3 H),
2.80 (t, J = 5.6 Hz, 1 H), 2.52–2.61 (m, 1 H), 2.07 (dd, J = 12.2,
6.6 Hz, 1 H), 1.78–1.90 (m, 2 H), 1.62 (s, 3 H), 1.13 (d, J = 6.3 Hz,
3 H), 0.93 (t, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.88 (d, J = 6.3 Hz,
3 H), 0.07 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
132.1, 130.9, 89.8, 70.1, 68.5, 60.8, 44.4, 33.7,29.7, 25.9, 20.1, 18.1,
16.8, 16.1, 15.4, –4.5, –4.6 ppm. HRMS (+ESI): calcd. for
C19H40O3NaSi [M + Na]+ 367.2639; found 367.2623.
to afford alcohol 7 (1.150 g, 78% yield) as a colorless oil. [α]2D0
+3.1 (c = 1.0, CHCl ). IR (neat): ν = 3423, 2957, 2931, 2858,
=
˜
3
max
1633, 1459, 1379, 1253, 1149, 1093, 1005, 928, 834, 774, 670 cm–1.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 5.41 (d, J = 9.0 Hz, 1 H),
3.99 (s, 2 H), 3.86 (quint, J = 6.0 Hz, 1 H), 3.44 (s, 3 H), 2.80 (t, J
= 5.3 Hz, 1 H), 2.54–2.65 (m, 1 H), 1.68 (s, 3 H), 1.11 (d, J =
6.0 Hz, 3 H), 0.95 (d, J = 6.0 Hz, 3 H),0.89 (s, 9 H), 0.06 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 132.8, 130.3, 89.2,
69.7, 69.0, 60.6, 33.4, 25.8, 19.8, 18.0, 15.5, 13.8, –4.6, –4.7 ppm.
HRMS (+ESI): calcd. for C16H34O3NaSi [M + Na]+ 325.2174;
found 325.2173.
tert-Butyl[(2R,3R,4S,8R,E)-3-methoxy-4,6,8-trimethyldeca-5,9-
dien-2-yloxy]dimethylsilane (3): IBX (0.061 g, 0.22 mmol) was dis-
solved in DMSO/CH2Cl2 (1:1, 3.0 mL) at 0 °C and to this was
added a solution of alcohol 32 (0.050 g, 0.14 mmol) in CH2Cl2
(2.0 mL) at the same temperature and stirred at r.t for 1 h. Then
the reaction mixture was diluted with diethyl ether and filtered
through a small pad of Celite. To this filtrate was added saturated
aqueous NaHCO3 solution and extracted with diethyl ether (2ϫ
5 mL). The combined organic extracts were dried with anhydrous
Na2SO4, filtered, and concentrated in vacuo to afford the corre-
sponding aldehyde (0.037 g, 75% yield) as colorless oil, which was
then subjected to Wittig olefination. To a suspension of
Ph3PCH3Br (0.178 g, 0.5 mmol) in THF (2.0 mL) at 0 °C, was
added nBuLi (0.2 mL, 2.5 m in THF, 0.49 mmol) dropwise through
a syringe. The resulting solution was warmed to room temperature
and then cooled to –78 °C over a period of 30 min. To this solution
was slowly added aldehyde (0.037 g, 0.11 mmol) in THF (1.0 mL)
through a cannula and the reaction mixture was warmed to room
temperature and stirred for 1 h. Then the reaction was quenched
with saturated NH4Cl solution (3 mL), the organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc (2ϫ 5 mL).
The combined organic layers were washed with brine (5 mL), dried
with Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (8% EtOAc/hexanes) to afford
olefin 3 as colorless oil (0.026 g, 72% yield). [α]2D0 = +8.2 (c = 0.25,
(S)-4-Benzyl-3-[(2R,6S,7R,8R,E)-8-(tert-butyldimethylsilyloxy)-7-
methoxy-2,4,6-trimethylnon-4-enoyl]oxazolidin-2-one (31): To a vig-
orously stirred solution of alcohol 7 (1.060 g, 3.5 mmol) in dry
THF (30 mL) at 0 °C was added imidazole (0.476 g, 7.0 mmol),
Ph3P (1.834 g, 7.0 mmol) and I2 (1.321 g, 5.2 mmol) in successive
portions. Stirring was continued at 0 °C for 5 min whereupon Et2O
(10 mL) was added to precipitate out Ph3P=O. The solids were fil-
tered off through a short pad of SiO2 and the filtrate was concen-
trated in vacuo to obtain crude allylic iodide 29 (1.244 g, 86%
yield). To a solution of sodium hexamethyldisilazide (NaHMDS;
4.2 mL, 4.2 mmol, 1.0 m in THF) in THF (5.0 mL) at –78 °C was
slowly added Evans’ auxiliary 30 (0.985 g, 4.2 mmol) in THF
(4.0 mL) through a cannula. The solution was stirred for 30 min
and then to it was added allylic iodide 29 (1.244 g, 3.0 mmol) in
THF (5 mL). The solution was stirred at –78 °C for 2.5 h and then
at –40 °C for 30 min and quenched with saturated aqueous NH4Cl
solution (30 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (3ϫ 30 mL). The combined or-
ganic layers were washed with brine (30 mL), dried with Na2SO4
and concentrated under vacuum. The crude product was purified
by silica gel column chromatography (10% EtOAc/hexanes) to give
31 (0.99 g, 65% yield) as a viscous liquid. [α]2D0 = –23.1(c = 1.30,
CHCl ). IR (neat): νmax = 2957, 2927, 2856, 1736, 1460, 1378, 1253,
˜
3
1096, 834, 772 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 5.65–
5.78 (m, 1 H), 5.13 (d, J = 9.0 Hz, 1 H), 4.85–5.01 (m, 2 H), 3.83
(quint, 1 H), 3.44 (s, 3 H), 2.77 (q, J = 5.8 Hz, 1 H), 2.48–2.61 (m,
1 H), 2.32 (dt, J = 13.6, 6.8 Hz, 1 H), 2.01 (dd, J = 13.6, 7.5 Hz, 1
H), 1.88 (dd, J = 13.6, 7.5 Hz, 1 H), 1.58 (d, J = 1.3 Hz, 3 H), 1.13
(d, J = 6.0 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.8 Hz,
3 H), 0.89 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 144.6, 131.6, 130.8, 111.9, 89.8, 70.1, 60.9, 47.2, 35.6,
33.7, 25.9, 20.2, 19.5, 18.1, 16.1, 15.4, –4.6 ppm. HRMS (+ESI):
calcd. for C20H40O2NaSi [M + Na]+ 363.2689; found 363.2693.
CHCl ). IR (neat): νmax = 2958, 2928, 2856, 1783, 1701, 1457, 1384,
˜
3
1245, 1211, 1096, 835, 774, 701 cm–1. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.19–7.36 (m, 5 H), 5.26 (d, J = 9.0 Hz, 1 H), 4.64–4.72
(m, 1 H), 4.11–4.22 (m, 2 H), 3.93–4.01 (m, 1 H), 3.82 (quint, J =
6.0 Hz, 1 H), 3.44 (s, 3 H), 3.29 (dd, J = 13.0, 3.0 Hz, 1 H), 2.79
(t, J = 5.0 Hz, 1 H), 2.69 (dd, J = 13.0, 9.0 Hz, 1 H), 2.52–2.60 (m,
2 H), 2.00 (dd, J = 13.0, 9.0 Hz, 1 H), 1.69 (s, 3 H), 1.14–1.07 (m,
6 H), 0.83–0.96 (m, 12 H), 0.06 (s, 6 H) ppm. 13C NMR (100 MHz, Methyl 2-{(2R,5S,6S)-6-[(2E,4E,6S,8E,10S,11R,12R)-12-(tert-But-
CDCl3, 25 °C): δ = 177.1, 153.1, 135.4, 132.3, 130.4, 129.5, 129.4, yldimethylsilyloxy)-11-methoxy-6,8,10-trimethyltrideca-2,4,8-trien-
128.9, 127.3, 89.7, 70.1, 66.0, 60.9, 55.3, 44.0, 38.1, 35.7, 33.8, 25.9, 2-yl]-5-methyltetrahydro-2H-pyran-2-yl}acetate (33): To a solution
20.1, 18.1, 16.3, 15.6, 15.2, –4.6 ppm. HRMS (+ESI): calcd. for of alkene 2 (0.021 g, 0.09 mmol) and 3 (0.010 g, 0.03 mmol) in dry
C29H47O5NNaSi [M + Na]+ 540.3116; found 540.3120.
CH2Cl2 (1.0 mL) was added Hoveyda–Grubbs second-generation
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4389–4397

A Formal Synthesis of Herboxidiene/GEX1A
2002, 55, 855; b) Y. Sakai, T. Tsujita, T. Akiyama, T. Yoshida,
T. Mizukami, S. Akinaga, S. Horinouchi, M. Yoshida, J. Anti-
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Y. Koguchi, M. Nishio, J. Kotera, K. Omori, T. Ohnuki, S.
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catalyst (3 mg). The reaction mixture was then stirred at room tem-
perature for 48 h. The reaction mixture was then concentrated in
vacuo and then directly purified by column chromatography (3%
EtOAc/hexanes) to afford a 14:1 (E/Z) mixture (by 1H NMR) of
33 (0.012 g, 76% yield) as a colorless oil. [α]2D0 = +8.1 (c = 0.30,
[4]
[5]
a) P. R. Blakemore, P. J. Kocienski, A. Morley, K. Muir, J.
Chem. Soc. Perkin Trans. 1 1999, 955; b) M. Banwell, M.
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CHCl ). IR (neat): νmax = 2955, 2927, 2857, 1742, 1455, 1375, 1225,
˜
3
1156, 1098, 1066, 834, 772 cm–1. 1H NMR (500 MHz, CDCl3,
25 °C): δ = 6.17 (dd, J = 14.8, 10.9 Hz, 1 H), 5.90 (d, J = 10.9 Hz,
1 H), 5.54 (dd, J = 14.8, 7.9 Hz, 1 H), 5.12 (d, J = 8.8 Hz, 1 H),
3.86–3.77 (m, 2 H), 3.66 (s, 3 H), 3.43 (s, 3 H), 3.32 (d, J = 9.9 Hz,
1 H), 2.78 (t, J = 5.5 Hz, 1 H), 2.60 (dd, J = 14.8, 5.9 Hz, 1 H),
2.56–2.50 (m, 1 H), 2.41 (d, J = 6.8 Hz, 1 H), 2.36 (dd, J = 14.2,
7.1 Hz, 1 H), 2.00 (dd, J = 12.8, 6.9 Hz, 1 H), 1.90 (dd, J = 6.9,
13.8 Hz, 1 H), 1.81–1.87 (m, 1 H), 1.70 (d, J = 0.9 Hz, 3 H), 1.64–
1.68 (m, 1 H), 1.58 (d, J = 1.0 Hz, 3 H), 1.50–1.57 (m, 1 H), 1.17–
1.38 (m, 2 H), 1.12 (d, J = 5.9 Hz, 3 H), 0.96 (d, J = 6.9 Hz, 3 H),
0.90 (s, 9 H), 0.69 (d, J = 6.9 Hz, 3 H), 0.06 (d, J = 2.9 Hz, 6
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.9, 140.6,
134.5, 131.5, 130.9, 128.5, 123.9, 90.6, 89.8, 73.8, 70.1, 61.1, 51.6,
47.6, 41.3, 35.3, 33.7, 32.3, 32.2, 31.7, 25.9, 20.2, 20.1, 18.2, 17.7,
16.3, 15.9, 12.3, –4.2 ppm. HRMS (+ESI): calcd. for CHO [M +
Na]+ 573.3946; found 573.3941.
[6]
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1
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Acknowledgments
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Fellowships.
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Received: March 10, 2014
Published Online: June 3, 2014
Eur. J. Org. Chem. 2014, 4389–4397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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