Enantiospecific formal total synthesis of iriomoteolide 3a

Article abstract of DOI:10.1002/asia.201402593

A formal total synthesis of the marine macrolide iriomoteolide 3a is described. Salient features of the synthesis include the elaboration of a β-keto phosphonate derived from d-(-)-tartaric acid and the extension of a chiral butyrolactone derived from L-g

Full text of DOI:10.1002/asia.201402593

FULL PAPER
DOI: 10.1002/asia.201402593
Enantiospecific Formal Total Synthesis of Iriomoteolide 3a
S. Mothish Kumar and Kavirayani R. Prasad*[a]
Abstract: A formal total synthesis of the marine macrolide iriomoteolide 3a is de-
scribed. Salient features of the synthesis include the elaboration of a b-keto phos-
phonate derived from d-(ꢀ)-tartaric acid and the extension of a chiral butyrolac-
tone derived from l-glutamic acid. Ring-closing metathesis is employed to con-
struct the macrolactone core of the natural product.
Keywords: iriomoteolide 3a
lactones macrocycles
products · total synthesis
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·
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natural
Introduction
The synthesis of the isopropylidene derivative of iriomoteo-
lide 3a, that is, 2, has also surfaced in the literature.[4a] In
continuation of our efforts in the total synthesis of macro-
lactone-containing natural products,[5] herein, we report
a formal approach to the synthesis of 1.
Iriomoteolide 3a (1, Figure 1) is a 15-membered marine
macrolide isolated by Tsudaꢀs group from the Amphidinium
strain HYA024 off the Iriomote island of Japan.[1] Iriomo-
teolide 3a (1) consists of a sensitive epoxide, a 3,4-dihy-
droxy-1,5-hexadiene unit, and a 1,4-pentadiene side chain.
Results and Discussion
Our approach for the synthesis of 1 was based on elabora-
tion of known Nevadoꢀs intermediate 3, the synthesis of
which was anticipated by ring-closing metathesis of ester 4.
Synthesis of the alcohol unit possessing the epoxy alkene
was envisaged from elaboration of hydroxy butyrolactone 7
(obtained from l-glutamic acid), whereas synthesis of the
acid fragment was planned by elaboration of b-keto phos-
phonate 6 derived from d-(ꢀ)-tartaric acid[6] and aldehyde 5
(Scheme 1).
Figure 1. Iriomoteolide 3a (1) and 7,8-O-isopropylidene 2.
Compound 1 and its isopropylidene derivative 2 were shown
to exhibit impressive cytotoxic activity against the lympho-
ma cell line DG-75 [half-maximal inhibitory concentration
(IC50)=0.08 and 0.02 mgmLꢀ1] and Raji cells (IC50 =0.05
and 0.02 mgmLꢀ1). Interestingly, deprotection of the aceto-
nide in 2 to parent macrolide 1 is problematic, and hence,
protection of the vicinal diol present in the macrolide with
other protecting groups is essential in the total synthesis. A
solitary total synthesis of 1 was reported by the Nevado
group,[2] whereas the synthesis of a macrocyclic core struc-
turally similar to that of 2 was reported by Reddyꢀs group.[3]
Scheme 1. Retrosynthesis of iriomoteolide 3a (1). TBS=tert-butyldimeth-
yl silyl; Bn=benzyl.
[a] S. M. Kumar, Prof. Dr. K. R. Prasad
Department of Organic Chemistry
Indian Institute of Science
Bangalore 560 012 (India)
Fax : (+91)8023600529
E-mail: prasad@orgchem.iisc.ernet.in
Accordingly, the synthetic sequence commenced with the
known Hosomi–Sakurai allylation of a,b-unsaturated-N-acy-
loxazolidinone 8 to furnish 9[7] possessing the requisite
methyl chiral center in 92% yield. The oxazolidinone in 9
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402593.
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S. Mothish Kumar, Kavirayani R. Prasad
was reduced with NaBH4 to yield the alcohol, which was
transformed into benzyl (Bn) ether 10 in 78% yield over
two steps. Treatment of the olefin in 10 with a catalytic
amount of OsO4 and N-methylmorpholine-N-oxide (NMO)
furnished the corresponding diol, which upon oxidative
cleavage with NaIO4 afforded crude aldehyde 5. Horner–
Wadsworth–Emmons olefination of aldehyde 5 with b-keto
phosphonate 6 derived from d-(ꢀ)-tartaric acid afforded
(E)-a,b-unsaturated ketone 11 in 76% yield. Reduction of
the ketone in 11 under Luche conditions afforded minor
erythro diastereomer 13[8] along with an inseparable mix-
ture of major threo diastereomer 12 and diol 14 resulting
from competing reduction of the Weinreb amide. Major
diastereomer 12 was isolated in pure form as tert-butyldi-
methylsilyl (TBS) ether 15 in 72% yield over two steps
(Scheme 2).
Reduction of the Weinreb amide in 15 with NaBH4 gave
alcohol 17 in 93% yield, which was transformed into iodide
18 in 87% yield. Treatment of 18 with freshly activated zinc
dust in refluxing ethanol furnished allyl alcohol 19 in excel-
lent yield. Protection of the free alcohol in 19 as TBS ether
20 under standard reaction conditions followed by deprotec-
tion of the primary benzyl group by using 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) at room temperature
furnished corresponding alcohol 21 in 68% yield (92%
based on recovered starting material).[9] Neither a longer re-
action time nor an increase in the temperature improved the
yield of product alcohol 21 in the debenzylation of 20 with
DDQ. Dess–Martin periodinane oxidation of alcohol 21 af-
forded the aldehyde, which was further oxidized under Pin-
nick conditions[10] to give acid fragment 22 in 94% yield
(Scheme 3).
Scheme 3. Synthesis of acid fragment 22. DDQ=2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone; DMP=Dess–Martin periodinane.
Synthesis of the alcohol fragment in ester 4 commenced
with the known stereoselective methylation of butyrolactone
23 derived from l-glutamic acid (Scheme 4).[11] By using
a strategy that was described earlier,[12] lactone 24 was trans-
formed into known alcohol 27 involving a sequence of re-
duction with LiBH4, protection of the formed 1,4-diol with
2,2-dimethoxypropane, and deprotection of the tert-butyldi-
phenylsilyl (TBDPS) group. Oxidation of 27 with Dess–
Martin periodinane furnished aldehyde 28, which upon
Keck allylation[13] by employing allyltributyltin in the pres-
ence of MgBr2·OEt2 gave threo allylic alcohol 29 as a single
diastereomer in 63% yield.
The hydroxy group in 29 was protected as its p-methoxy-
benzyl (PMB) ether by using NaH and PMBCl, which upon
subsequent treatment with silica gel led to the deprotection
Scheme 2. Synthesis of Weinreb amide 15. TBS=tert-butyldimethyl silyl;
NMO=N-methylmorpholine-N-oxide.
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S. Mothish Kumar, Kavirayani R. Prasad
Scheme 4. Synthesis of alcohol 29. TBDPS=tert-butyldiphenylsilyl; 2,2-
DMP=2,2-dimethoxypropane; CSA=camphorsulfonic acid; TBAF=
tetra-butylammonium fluoride; DMP=Dess–Martin periodinane.
of the acetonide[14] to afford 1,4-diol 30 in 95% yield
(Scheme 5). Diol 30 was reprotected as bis-TBS ether 31,
which upon olefin cross-metathesis with methyl acrylate by
using Grubbs second-generation catalyst afforded unsaturat-
ed ester 32 in 84% yield. Reduction of the ester in 32 with
diisobutylaluminum hydride (DIBAL-H) furnished allyl al-
cohol 33 in 92% yield. Sharpless asymmetric epoxidation of
allyl alcohol 33 afforded epoxide 34 in 94% yield. Oxidation
of the alcohol in 34 by using SO3·Py (Py=pyridine) gave the
aldehyde, which under Wittig olefination conditions pro-
duced olefin 35 in 74% yield. Finally, the PMB group was
cleanly deprotected with DDQ to give known alcohol 36[15]
in 89% yield. Esterification of alcohol 36 and acid fragment
22 under Yamaguchi conditions[16] furnished ester 4 in 84%
yield. Ring-closing metathesis of 4 with Grubbs second-gen-
eration catalyst afforded macrolactone 37 in 66% yield. The
primary TBS group in 37 was selectively deprotected by
using NH4F in MeOH to give known Nevadoꢀs key inter-
mediate 3 in 50% yield (77% based on recovered starting
material). The spectral and physical data of 3 were in agree-
ment with those reported by Nevadoꢀs group.[2] Given that
the conversion of 3 into iriomoteolide 3a (1) was reported
by Nevadoꢀs group, the present sequence constitutes
a formal total synthesis of 1.
Scheme 5. Formal total synthesis of iriomoteolide 3a (1). PMB=p-me-
thoxybenzyl; TBS=tert-butyldimethylsilyl; DIBAL-H=diisobutylalumi-
num hydride; DIPT=diisopropyl tartrate; DIPEA=diisopropylethyla-
mine; NaHMDS=sodium hexamethyldisilazide; DMAP=N,N-dimethy-
laminopyridine.
Conclusions
Experimental Section
In conclusion, a formal approach to iriomoteolide 3a is pre-
sented from the b-ketophosphonate derived from d-(ꢀ)-tar-
taric acid. Salient features of the synthesis include Hosomi–
Sakurai allylation, Keck allylation, Horner–Wadsworth–
Emmons olefination, olefin cross-metathesis, and ring-clos-
ing metathesis reactions.
General methods
Column chromatography was performed on Acmeꢀs silica gel, 100–200
mesh. TLC plates were visualized either with UV, in an iodine chamber,
or with phosphomolybdic acid spray. Unless stated otherwise, all reagents
were purchased from commercial sources and were used without addi-
tional purification. Dichloromethane was freshly distilled with calcium
hydride before use. THF was freshly distilled with Na-benzophenone
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S. Mothish Kumar, Kavirayani R. Prasad
ketyl. Petroleum ether refers to the fraction boiling at 60–808C. Optical
rotations were recorded at 248C. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded with a 400 MHz machine in CDCl3 as
solvent, and the chemical shifts are reported in ppm from the residual
solvent as an internal standard. HRMS was obtained by using a Micro-
mass-Q-TOF machine, operating in the electrospray ionization (ESI)
mode. Unless stated otherwise, all reactions were performed under an
inert atmosphere.
stirred at the same temperature for 1 h. Upon completion of the reaction
(monitored by TLC), the mixture was filtered through a short pad of
Celite, and the Celite pad was washed with CH2Cl2 (20 mL). Evaporation
of the solvent gave crude aldehyde 5, which was used as such in the next
reaction without further purification.
Cs2CO3 (0.81 g, 2.47 mmol) was added to a solution of b-keto phospho-
nate 6 (0.56 g, 1.65 mmol) in iPrOH (10 mL), and the mixture was stirred
at room temperature for 45 min. The mixture was then cooled to 08C
and a freshly prepared solution of aldehyde 5 (obtained above) in iPrOH
(5 mL) was added dropwise. The mixture was then stirred at the same
temperature for 1 h. Upon completion of the reaction (monitored by
TLC), 10% citric acid solution (20 mL) was added, and the mixture was
extracted with EtOAc (2ꢂ20 mL). The combined organic layer was
washed with brine (10 mL) and dried with anhydrous Na2SO4. Evapora-
tion of the solvent gave a crude residue, which upon purification by silica
gel column chromatography (petroleum ether/EtOAc=3:2) furnished
ketone 11 (0.55 g, 76%) as a colorless oil. ½aꢁ2D4 = +4.3 (c=1.2, CHCl3);
Syntheses
9: TiCl4 (1.0 mL, 8.65 mmol) was added dropwise to
a precooled
(ꢀ788C) solution of oxazolidinone (1.0 g, 4.33 mmol) in CH2Cl2
8
(45 mL), and the mixture was stirred at the same temperature for 20 min.
Allyltrimethylsilane (1.8 mL, 10.83 mmol) was introduced into the mix-
ture, which was stirred at ꢀ788C for another 2 h. Upon completion of
the reaction (monitored by TLC), it was quenched by the addition of a sa-
turated aqueous solution of NaHCO3 (30 mL), and the mixture was ex-
tracted with EtOAc (2ꢂ20 mL). The combined organic extract was
washed with brine (20 mL) and dried with anhydrous Na2SO4. Evapora-
tion of the solvent gave the crude residue, which was purified by silica
gel column chromatography (petroleum ether/EtOAc=3:7) to furnish 9
(1.09 g, 92%) as a colorless oil. ½aꢁ2D4 = +29.1 (c=1.5, CHCl3); IR (neat):
IR (neat): n˜ =2936, 2872, 1720, 1672, 1090 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.40–7.20 (m, 5H), 7.04 (dt, J=15.6, 7.2 Hz, 1H), 6.45 (d, J=
15.6 Hz, 1H), 5.13 (brs, 1H), 4.97 (brd, J=4.4 Hz, 1H), 4.48 (s, 2H),
3.69 (s, 3H), 3.73–3.40 (m, 2H), 3.21 (s, 3H), 2.34–2.21 (m, 1H), 2.17–
2.03 (m, 1H), 1.23–1.78 (m, 1H), 1.63 (dt, J=13.6, 6.8 Hz, 1H), 1.51 (s,
3H), 1.51–1.44 (m, 1H), 1.26 (s, 3H), 0.91 ppm (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=196.0, 170.0, 149.3, 138.4, 128.4 (2C),
127.62 (2C), 127.60, 127.3, 112.9, 81.4, 74.3, 72.9, 68.1, 61.6, 40.2, 36.4,
32.5, 29.6, 26.7, 26.4, 19.5 ppm; HRMS (ESI): m/z: calcd for C23H33NO6 +
Na+: 442.2206; found: 442.2203.
n˜ =3071, 2962, 1782, 1706, 1384, 1198 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d=7.39–7.26 (m, 5H), 5.78–5.68 (m, 1H), 5.42 (dd, J=8.8, 3.6 Hz, 1H),
5.00–4.96 (m, 2H), 4.66 (t, J=8.8 Hz, 1H), 4.25 (dd, J=8.8, 3.6 Hz, 1H),
3.00–2.66 (m, 2H), 2.13–2.02 (m, 2H), 1.97–1.90 (m, 1H), 0.89 ppm (d,
J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.2, 153.7, 139.2,
136.5, 129.2 (2C), 128.7, 125.9 (2C), 116.5, 69.8, 57.6, 41.7, 40.8, 29.5,
19.6 ppm; HRMS (ESI): m/z: calcd for C16H19NO3 +Na+: 296.1263;
found: 296.1263.
12: CeCl3·7H2O (0.71 g, 1.9 mmol) was added to a solution of 11 (0.55 g,
1.27 mmol) in MeOH (15 mL), and the mixture was stirred at room tem-
perature for 45 min. The mixture was then cooled to ꢀ788C and NaBH4
(0.073 g, 1.9 mmol) was added portionwise. The resulting mixture was
then stirred at the same temperature for 1 h. Upon completion of the re-
action (monitored by TLC), it was quenched by the addition of water
(1 mL) at ꢀ788C, and the mixture was slowly warmed up to room tem-
perature. The mixture was then poured into water (10 mL) and extracted
with EtOAc (2ꢂ5 mL). The combined organic layer was washed with
brine (5 mL) and dried with anhydrous Na2SO4. Evaporation of the sol-
vent gave the crude residue, which was purified by silica gel column chro-
matography (petroleum ether/EtOAc=1:1) to furnish minor diastereo-
mer 13 (0.04 g, 7%) as a colorless oil and a nonseparable mixture of 12
and 14 (0.47 g).
10: NaBH4 (0.84 g, 22.0 mmol) was added at 08C to a solution of oxazoli-
dinone 9 (1.2 g, 4.4 mmol) in THF/H2O (5:1, 25 mL), and the mixture
was stirred at room temperature. Upon completion of the reaction, it was
quenched with aqueous 2n HCl (4 mL) and extracted with diethyl ether
(2ꢂ20 mL). The combined organic layer was washed with brine (10 mL)
and dried with anhydrous Na2SO4. Evaporation of the solvent gave the
crude residue, which was used as such in the next step without further
purification.
NaH (60% dispersion in mineral oil, 0.26 g, 6.6 mmol) was added to
a precooled (08C) solution of the crude alcohol obtained above in THF/
DMF (4:1, 6 mL), and the mixture was stirred for 0.5 h. Benzyl bromide
(0.68 mL, 5.72 mmol) was introduced into the mixture, which was stirred
at room temperature for another 2 h. Upon completion of the reaction
(TLC), it was quenched with ice cold water (5 mL), and the mixture was
extracted with diethyl ether (2ꢂ20 mL). The combined organic layer was
washed with brine (10 mL) and dried with anhydrous Na2SO4. Evapora-
tion of the solvent gave a crude residue, which upon purification by silica
gel column chromatography (petroleum ether/Et2O=9:1) gave benzyl
ether 10 (0.69 g, 78% over 2 steps) as a colorless oil. ½aꢁ2D4 = +5.0 (c=0.4,
Minor diastereomer 13: ½aꢁ2D4 =ꢀ4.5 (c=1.0, CHCl3); IR (neat): n˜ =3470,
2935, 1719, 1667 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.34–7.26 (m,
;
5H), 5.78 (dt, J=15.2, 7.2 Hz, 1H), 5.43 (dd, J=15.2, 5.2 Hz, 1H), 4.74
(brs, 1H), 4.60 (brs, 1H), 4.49 (s, 2H), 4.42–4.32 (m, 1H), 3.72 (s, 3H),
3.55–3.43 (m, 2H), 3.12 (s, 3H), 2.37 (s, 1H), 2.09–2.03 (m, 1H), 1.92–
1.81 (m, 1H), 1.70–1.63 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.45–1.38 (m,
1H), 0.85 ppm (d, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
170.2, 138.5, 132.9, 128.3 (3C), 127.6 (2C), 127.5, 111.0, 80.3, 72.9, 72.0,
70.9, 68.4, 61.8, 39.8, 36.2, 32.3, 29.8, 26.9, 26.0, 19.3 ppm; HRMS (ESI):
m/z: calcd for C23H35NO6 +Na+: 444.2362; found: 444.2360.
CHCl3); IR (neat): n˜ =3067, 2932, 2863, 1600 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.33–7.23 (m, 5H), 5.85–5.74 (m, 1H), 5.02–4.96 (m, 2H),
4.48 (s, 2H), 3.57–3.43 (m, 2H), 2.15–2.00 (m, 1H), 1.98–1.82 (m, 1H),
1.74–1.61 (m, 2H), 1.50–1.35 (m, 1H), 0.88 ppm (d, J=6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=138.6, 137.2, 128.3 (2C), 127.6 (2C),
127.4, 115.8, 72.8, 68.5, 41.4, 36.2, 29.7, 19.4 ppm; HRMS (ESI): m/z:
calcd for C14H20O+Na+: 227.1412; found: 227.1413.
15: 2,6-Lutidine (0.27 mL, 2.23 mmol) and tert-butyldimethylsilyl triflate
(0.3 mL, 1.34 mmol) were added to a precooled (08C) solution of 12/14
(0.47 g, obtained above) in CH2Cl2 (10 mL). The mixture was stirred at
room temperature for 1 h. Upon completion of the reaction (TLC), the
mixture was diluted with EtOAc (2ꢂ10 mL) and washed with a saturated
aqueous solution of NaHCO3 (10 mL). The combined organic extract was
dried with anhydrous Na2SO4. Evaporation of the solvent under reduced
pressure gave the crude residue, which upon purification by silica gel
column chromatography (petroleum ether/EtOAc=7:3) furnished 15
(0.49 g, 72% for 2 steps) as a colorless oil. ½aꢁ2D4 = +7.7 (c=2.2, CHCl3);
11: OsO4 (0.004 g, 0.02 mmol) and NMO (0.57 g, 4.9 mmol) were added
at room temperature to a solution of benzyl ether 10 (0.4 g, 1.96 mmol)
in acetone/H2O (10 mL, 4:1), and the mixture was stirred for 4 h at the
same temperature. Upon completion of the reaction (monitored by
TLC), a saturated aqueous solution of Na2SO3 (10 mL) was added, and
the mixture was stirred for 0.5 h. The mixture was extracted with EtOAc
(2ꢂ10 mL), and the combined organic layer was washed with brine
(10 mL) and dried with anhydrous Na2SO4. Evaporation of the solvent
gave the crude residue, which was used as such in the next reaction with-
out further purification.
IR (neat): n˜ =2931, 2858, 1673, 1381, 1097 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.34–7.26 (m, 5H), 5.69 (dt, J=15.2, 7.2 Hz, 1H), 5.55 (dd,
J=15.2, 5.6 Hz, 1H), 4.72 (brs, 1H), 4.61–4.51 (m, 1H), 4.49 (s, 2H), 4.35
(t, J=5.2 Hz, 1H), 3.71 (s, 3H), 3.55–3.46 (m, 2H), 3.19 (s, 3H), 2.17–
2.02 (m, 1H), 1.99–1.84 (m, 1H), 1.76–1.60 (m, 2H), 1.48–1.40 (m, 1H),
1.45 (s, 3H), 1.43 (s, 3H), 0.89 (d, J=3.6 Hz, 3H), 0.86 (s, 9H), 0.05 (s,
3H), 0.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=170.4, 138.6,
NaIO4 (0.63 g, 2.94 mmol) was added to a precooled (08C) solution of
the diol obtained above in MeOH/H2O (9:1, 8 mL), and the mixture was
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S. Mothish Kumar, Kavirayani R. Prasad
131.3, 129.8, 128.3 (2C), 127.6 (2C), 127.5, 111.4, 80.8, 72.9, 72.6, 72.3,
68.5, 61.8, 39.7, 36.3, 32.2, 30.0, 27.0, 26.3, 25.7 (3C), 19.3, 18.2, ꢀ4.5,
ꢀ4.9 ppm; HRMS (ESI): m/z: calcd for C29H49NO6Si+Na+: 558.3227;
found: 558.3229.
15.2, 5.6 Hz, 1H), 5.32 (d, J=17.2 Hz, 1H), 5.18 (d, J=10.8 Hz, 1H),
4.51 (s, 2H), 3.99–3.86 (m, 2H), 3.60–3.42 (m, 2H), 3.63 (d, J=2.4 Hz,
1H), 2.17–2.02 (m, 1H), 1.97–1.81 (m, 1H), 1.82–1.59 (m, 2H), 1.52–1.37
(m, 1H), 0.91 (s, 9H), 0.89 (d, J=6.4 Hz, 3H), 0.09 (s, 3H), 0.06 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=138.6, 136.9, 132.3, 131.0, 128.3
(2C), 127.6 (2C), 127.5, 116.4, 77.4, 75.9, 72.8, 68.4, 39.6, 36.4, 29.9, 25.9
(3C), 19.4, 18.1, ꢀ3.9, ꢀ4.8 ppm; HRMS (ESI): m/z: calcd for
C24H40O3Si+Na+: 427.2644; found: 427.2646.
16: Colorless oil (0.08 g, 11%). ½aꢁ2D4 = +3.87 (c=0.8, CHCl3); IR (neat):
n˜ =2955, 2931, 2858, 1465, 1254 cmꢀ1 1H NMR (400 MHz, CDCl3): d=
;
7.33–7.25 (m, 5H), 5.70–5.63 (m, 1H), 5.55 (dd, J=15.2, 6.0 Hz, 1H),
4.51 (s, 2H), 4.31 (t, J=5.2 Hz, 1H), 4.06–3.98 (m, 1H), 3.90 (dd, J=7.6,
4.4 Hz, 1H), 3.81 (dd, J=11.2, 3.2 Hz, 1H), 3.69 (dd, J=11.2, 4.4 Hz,
1H), 3.55–3.45 (m, 2H), 2.19–2.07 (m, 1H), 1.92 (quint., J=6.8 Hz, 1H),
1.74–1.62 (m, 2H), 1.51–1.45 (m, 1H), 1.41 (s, 3H), 1.39 (s, 3H), 0.92 (s,
21H), 0.06 (s, 9H), 0.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
138.6, 131.1, 130.4, 128.3 (2C), 127.5 (2C), 127.4, 109.0, 80.0, 77.9, 73.3,
72.8, 68.5, 64.2, 39.7, 36.3, 30.0, 27.3, 27.2, 26.0 (3C), 25.9 (3C), 19.4, 18.4,
18.2 ꢀ4.4, ꢀ4.8, ꢀ5.2, ꢀ5.3 ppm; HRMS (ESI): m/z: calcd for
C33H60O5Si2 +Na+: 615.3877; found: 615.3875.
20: 2,6-Lutidine (0.16 mL, 1.29 mmol) and tert-butyldimethylsilyl triflate
(0.18 mL, 0.78 mmol) were added at 08C to a solution of alcohol 19
(0.21 g, 0.52 mmol) in CH2Cl2 (4 mL). The mixture was stirred at room
temperature for 1 h. Upon completion of the reaction, the mixture was
diluted with EtOAc (2ꢂ10 mL) and washed with a saturated aqueous so-
lution of NaHCO3 (10 mL). The combined organic extract was dried with
anhydrous Na2SO4. Evaporation of the solvent under reduced pressure
gave the crude residue, which upon purification by silica gel column chro-
matography (petroleum ether) furnished 20 (0.26 g, 96%) as a colorless
oil. ½aꢁ2D4 =ꢀ34.9 (c=2.4, CHCl3); IR (neat): n˜ =2930, 2858, 1461, 1363,
17: NaBH4 (0.57 g, 14.9 mmol) was added portionwise to a precooled
(08C) solution of Weinreb amide 15 (0.41 g, 0.75 mmol) in MeOH
(10 mL), and the mixture was stirred at room temperature for 2 h. Upon
completion of the reaction (monitored by TLC), it was quenched by the
addition of water (10 mL), and the mixture was extracted with EtOAc
(2ꢂ20 mL). The combined organic extract was washed with brine
(10 mL) and dried with anhydrous Na2SO4. Evaporation of the solvent
gave the crude residue, which was purified by silica gel column chroma-
tography (petroleum ether/EtOAc=2:3) to furnish 17 (0.33 g, 93%) as
a colorless oil. ½aꢁ2D4 =ꢀ10.9 (c=2.0, CHCl3); IR (neat): n˜ =3479, 2931,
1
1098 cmꢀ1; H NMR (400 MHz, CDCl3): d=7.36–7.26 (m, 5H), 5.91 (ddd,
J=17.2, 10.8, 4.4 Hz, 1H), 5.55 (dt, J=15.2, 6.8 Hz, 1H), 5.44 (dd, J=
15.2, 6.0 Hz, 1H), 5.21 (d, J=17.2 Hz, 1H), 5.12 (d, J=10.8 Hz, 1H),
4.52 (s, 2H), 4.15–4.00 (m, 2H), 3.58–3.46 (m, 2H), 2.17–2.02 (m, 1H),
1.94–1.80 (m, 1H), 1.77–1.61 (m, 2H), 1.53–1.38 (m, 1H), 0.93–0.89 (m,
21H), 0.09 (s, 6H), 0.07 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
138.7, 137.5, 130.5, 130.2, 128.3 (2C), 127.5 (2C), 127.4, 115.0, 76.3, 76.2,
72.9, 68.6, 39.7, 36.3, 29.9, 25.9 (6C), 19.4, 18.2 (2C), ꢀ4.4, ꢀ4.6, ꢀ4.7,
ꢀ4.8 ppm; HRMS (ESI): m/z: calcd for C30H54O3Si2 +Na+: 541.3509;
found: 541.3504.
2858, 1457, 1103 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.33–7.26 (m,
;
5H), 5.68 (dt, J=15.6, 7.6 Hz, 1H), 5.51 (dd, J=15.6, 5.6 Hz, 1H), 4.49
(s, 2H), 4.37 (t, J=5.2 Hz, 1H), 4.09–3.93 (m, 1H), 3.80 (dd, J=8.0,
4.8 Hz, 1H), 3.74–3.62 (m, 2H), 3.57–3.44 (m, 2H), 2.60 (dd, J=7.2,
5.6 Hz, 1H), 2.18–2.05 (m, 1H), 1.92 (quint., J=6.8 Hz, 1H), 1.72–1.39
(m, 2H), 1.43–1.30 (m, 1H), 1.40 (s, 3H), 1.36 (s, 3H), 0.95–0.83 (s, 12H),
0.09 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=138.5,
131.9, 129.2, 128.3 (2C), 127.6 (2C), 127.5, 108.9, 81.1, 77.3 (2C), 72.8,
68.4, 63.2, 39.7, 36.2, 30.1, 27.1, 26.9, 25.7 (3C), 19.5, 18.2, ꢀ4.6,
ꢀ5.0 ppm; HRMS (ESI): m/z: calcd for C27H46O5Si+Na+: 501.3012;
found: 501.3016.
21: DDQ (0.088 g, 0.39 mmol) was added to a solution of 20 (0.1 g,
0.19 mmol) in CH2Cl2/phosphate buffer (4 mL, 19:1), and the resulting
mixture was stirred at room temperature for 2 h. Progress of the reaction
was monitored by TLC, and after 2 h, the mixture was diluted with a satu-
rated aqueous solution of NaHCO3 (5 mL) and extracted with EtOAc
(2ꢂ10 mL). (Partial conversion of the starting material into the product
was observed by TLC; petroleum ether/EtOAc=9:1, Rf =0.3; stirring for
a longer time led to decomposition). The combined organic layer was
dried with anhydrous Na2SO4, and the residue obtained after evaporation
of the solvent was purified by silica gel column chromatography (petrole-
um ether) to give recovered starting material 20 (0.026 g, 26%) and alco-
hol 21 (0.056 g, 68%, 92% based on recovered starting material) as a col-
orless oil. ½aꢁ2D4 =ꢀ47.9 (c=2.0, CHCl3); IR (neat): n˜ =3405, 2931, 2858,
18: Triphenylphosphine (0.26 g, 1.0 mmol), imidazole (0.09 g, 1.34 mmol),
and iodine (0.26 g, 1.0 mmol) were added at room temperature to a solu-
tion of 17 (0.32 g, 0.67 mmol) in dry THF (4 mL), and the mixture was
stirred at the same temperature for 3 h. Upon completion of the reaction
(TLC), the mixture was poured into water (10 mL) and extracted with
EtOAc (2ꢂ20 mL). The combined organic layer was washed with saturat-
ed sodium thiosulfate solution (10 mL) and brine (10 mL) and dried with
anhydrous Na2SO4. Silica gel column chromatography (petroleum ether/
EtOAc=9:1) of the residue obtained after evaporation of the solvent
gave iodide 18 (0.34 g, 87%) as a colorless oil. ½aꢁ2D4 = +10.6 (c=1.6,
1461, 1116 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.90 (ddd, J=17.2,
;
10.8, 4.8 Hz, 1H), 5.52 (dt, J=15.6, 7.2 Hz, 1H), 5.41 (dd, J=15.6,
5.2 Hz, 1H), 5.18 (d, J=17.6 Hz, 1H), 5.10 (d, J=10.4 Hz, 1H), 4.13–4.00
(m, 2H), 3.74–3.61 (m, 2H), 2.14–2.00 (m, 1H), 1.98–1.81 (m, 1H), 1.70–
1.53 (m, 2H), 1.46–1.33 (m, 1H), 1.20 (s, 1H), 0.96–0.84 (m, 21H), 0.074
(s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.046 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=137.4, 130.6, 130.0, 114.9, 76.2, 76.1, 61.1, 39.7,
39.4, 29.6, 25.8 (6C), 19.4, 18.2, 18.1, ꢀ4.5, ꢀ4.68, ꢀ4.74, ꢀ4.8 ppm;
HRMS (ESI): m/z: calcd for C23H48O3Si2 +Na+: 451.3040; found:
451.3037.
CHCl3); IR (neat): n˜ =2956, 2930, 2858, 1459, 1370, 1073 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=7.38–7.20 (m, 5H), 5.68 (dt, J=15.2, 7.2 Hz, 1H),
5.50 (dd, J=15.2, 6.0 Hz, 1H), 4.49 (s, 2H), 4.33 (brs, 1H), 3.81–3.68 (m,
2H), 3.56–3.45 (m, 2H), 3.43 (dd, J=8.8, 2.4 Hz, 1H), 3.27 (dd, J=10.4,
4.0 Hz, 1H), 2.19–2.04 (m, 1H), 1.20–1.84 (m, 1H), 1.79–1.61 (m, 2H),
1.45 (s, 3H), 1.45–1.31 (m, 1H), 1.36 (s, 3H), 0.95–0.85 (s, 12H), 0.09 (s,
3H), 0.05 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=138.6, 131.8,
129.6, 128.3 (2C), 127.6 (2C), 127.5, 109.3, 83.4, 75.7, 72.8, 72.7, 68.4,
39.7, 36.3, 30.0, 27.6, 27.3, 25.8 (3C), 19.5, 18.2, 8.3, ꢀ4.6, ꢀ4.8 ppm;
HRMS (ESI): m/z: calcd for C27H45IO4Si+Na+: 611.2030; found:
611.2029.
22: NaHCO3 (0.053 g, 0.63 mmol) and Dess–Martin periodinane (0.13 g,
0.32 mmol) were added at 08C to a stirred solution of alcohol 21 (0.09 g,
0.21 mmol) in dry CH2Cl2 (4 mL). The mixture was warmed to room tem-
perature and stirred for 2 h at the same temperature. Upon completion
of the reaction (TLC), it was quenched with a saturated aqueous solution
of NaHCO3 (5 mL) and Na2S2O3 (5 mL), and the mixture was diluted
with Et2O (10 mL). The aqueous phase was extracted with Et2O (2ꢂ
10 mL). The combined organic layer was washed with brine (10 mL),
dried with anhydrous Na2SO4, and concentrated. The crude aldehyde
thus obtained as a yellow oil was used as such in the next step without
further purification.
19: Zinc dust (0.74 g, 11.2 mmol) was added at room temperature to a so-
lution of iodide 18 (0.33 g, 0.56 mmol) in absolute ethanol (4 mL), and
the mixture was heated at reflux for 1 h. Upon completion of the reaction
(TLC), the mixture was filtered through a short pad of Celite, and the
Celite pad was washed with CH2Cl2 (20 mL). Silica gel column chroma-
tography (petroleum ether/EtOAc) of the residue obtained after evapo-
ration of the solvent furnished alcohol 19 (0.218 g, 96%) as a colorless
oil. ½aꢁ2D4 = +1.6 (c=1.5, CHCl3); IR (neat): n˜ =3478, 2930, 2859, 1461,
Phosphate buffer (1 mL, pHꢂ3.6) and 2-methyl-2-butene (0.07 mL,
0.63 mmol) were added at room temperature to a stirred solution of the
aldehyde obtained above in tBuOH (2 mL).
A solution of NaClO2
(0.057 g, 0.63 mmol) in H2O (1 mL) was added to the mixture, which was
stirred at room temperature for 3 h. Upon completion of the reaction
(TLC), the mixture was acidified with 1n HCl to pH 4. Most of the sol-
1
1101 cmꢀ1; H NMR (400 MHz, CDCl3): d=7.35–7.22 (m, 5H), 5.84 (ddd,
J=17.2, 10.8, 6.4 Hz, 1H), 5.62 (dt, J=15.2, 7.2 Hz, 1H), 5.41 (dd, J=
Chem. Asian J. 2014, 9, 3431 – 3439
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S. Mothish Kumar, Kavirayani R. Prasad
vent was evaporated off, and the mixture was diluted with EtOAc (5 mL)
IR (neat): n˜ =2936, 2862, 1383, 1219, 1080 cmꢀ1 1H NMR (400 MHz,
;
and brine (5 mL). The organic layer was separated off, and the aqueous
layer was extracted with EtOAc (2ꢂ10 mL). The combined organic ex-
tract was dried with anhydrous Na2SO4, and the residue thus obtained
after evaporation of the solvent was purified by silica gel column chroma-
tography (petroleum ether/EtOAc=4:1) to afford 22 (0.088 g, 94%) as
a colorless oil. ½aꢁ2D4 =ꢀ43.8 (c=1.5, CHCl3); IR (neat): n˜ =3432, 2932,
CDCl3): d=7.78–7.64 (m, 4H), 7.50–7.32 (m, 6H), 3.97–3.85 (m, 2H),
3.66 (dd, J=10.4, 6.8 Hz, 1H), 3.50 (dd, J=10.4, 6.0 Hz, 1H), 3.38 (d, J=
12.0 Hz, 1H), 1.95–1.80 (m, 1H), 1.60–1.47 (m, 1H), 1.54–1.35 (m, 1H),
1.34 (s, 3H), 1.28 (s, 3H), 1.07 (s, 9H), 1.06 ppm (d, J=8.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=135.7 (2C), 135.6 (2C), 133.7 (2C),
129.6 (2C), 127.6 (4C), 100.6, 68.8, 67.2, 65.9, 37.5, 31.0, 26.8 (3C), 25.01,
25.00, 19.2, 17.1 ppm; HRMS (ESI): m/z: calcd for C25H36O3Si+Na+:
435.2331; found: 435.2332.
2860, 1713, 1078 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.89 (ddd, J=
;
17.2, 10.8, 4.4 Hz, 1H), 5.53 (dt, J=15.2, 6.8 Hz, 1H), 5.45 (dd, J=15.2,
5.2 Hz, 1H), 5.19 (d, J=17.2 Hz, 1H), 5.11 (d, J=10.8 Hz, 1H), 4.16–4.01
(m, 2H), 2.41 (dd, J=15.2, 5.2 Hz, 1H), 2.19–1.91 (m, 4H), 0.97 (d, J=
6.0 Hz, 3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H), 0.053 (s, 3H),
0.048 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=179.5, 137.3, 131.5,
128.9, 115.1, 76.2, 75.9, 40.7, 39.3, 30.1, 25.8 (6C), 19.4, 18.2, 18.1, ꢀ4.5,
ꢀ4.67, ꢀ4.75, ꢀ4.8 ppm; HRMS (ESI): m/z: calcd for C23H46O4Si2 +Na+:
465.2832; found: 465.2839.
27: tetra-Butylammonium fluoride (1.0m in THF, 6.8 mL, 6.8 mmol) was
added at 08C to a solution of 26 (2.34 g, 5.70 mmol) in THF (15 mL), and
the mixture was stirred at room temperature for 2 h. Upon completion of
the reaction (TLC), it was diluted with cold water, and the mixture was
extracted with EtOAc (2ꢂ20 mL). The combined organic extract was
washed with brine (20 mL) and dried with anhydrous Na2SO4. Evapora-
tion of the solvent followed by silica gel column chromatography (petro-
leum ether/EtOAc=3:2) of the crude residue furnished 27 (0.84 g, 89%)
as a colorless oil. ½aꢁ2D4 = +13.27 (c=1.1, CHCl3); IR (neat): n˜ =3451,
24: nBuLi (4.9 mL, 7.26 mmol) was added dropwise at 08C to a solution
of diisopropylamine (1.02 mL, 7.26 mmol) in THF (10 mL), and the mix-
ture was stirred at the same temperature for 0.5 h. The mixture was
cooled to ꢀ788C, and a solution of lactone 23[9] (2.3 g, 6.50 mmol) in
THF (15 mL) was added dropwise; the mixture was then stirred for an-
other 30 min. MeI (0.61 mL, 9.9 mmol) was introduced into the mixture,
which was stirred for another 30 min at the same temperature. Upon
completion of the reaction (indicated by TLC), it was quenched with a sa-
turated aqueous solution of NH4Cl (20 mL). The mixture was extracted
with EtOAc (2ꢂ30 mL) and washed with brine (20 mL). The combined
organic extract was dried with anhydrous Na2SO4, and the residue thus
obtained after evaporation of the solvent was purified by silica gel
column chromatography (petroleum ether/EtOAc=9:1) to afford 25
(1.99 g, 82%) as a white solid. M.p. 75–778C (Ref. [9c] m.p. 76–778C).
½aꢁ2D4 = +34.1 (c=1.0, CHCl3) {Ref. [9c] ½aꢁD25 = +35.0 (c=2.0, CHCl3)};
2937, 1380, 1221, 1064, 741 cmꢀ1 1H NMR (400 MHz, CDCl3): d=4.05–
;
3.90 (m, 1H), 3.89 (d, J=12.0 Hz, 1H), 3.51–3.36 (m, 2H), 3.38 (d, J=
12.0 Hz, 1H), 2.13 (brs, 1H), 1.90–1.80 (m, 1H), 1.58–1.40 (m, 1H), 1.35
(s, 6H), 1.29 (d, J=14.0 Hz, 1H) 1.06 ppm (d, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=101.0, 68.9, 66.0, 65.9, 37.1, 30.8, 25.3, 24.9,
17.0 ppm; HRMS (ESI): m/z: calcd for C9H18O3 +Na+: 197.1154; found:
197.1155.
29: NaHCO3 (1.02 g, 12.2 mmol) and Dess–Martin periodinane (2.58 g,
6.10 mmol) were added at 08C to
a solution of alcohol 27 (0.7 g,
4.07 mmol) in dry CH2Cl2 (20 mL). The mixture was warmed to room
temperature and stirred for 1 h. Upon completion of the reaction (TLC),
it was quenched with a saturated aqueous solution of NaHCO3 (10 mL)
and Na2S2O3 (10 mL), and the mixture was diluted with diethyl ether
(30 mL). The aqueous phase was extracted with Et2O (2ꢂ20 mL). The
combined organic layer was washed with water (20 mL) and brine
(20 mL) and dried with anhydrous Na2SO4. Evaporation of solvent gave
crude aldehyde 28 as a yellow oil, which was used as such in the next
step without further purification.
IR (neat): n˜ =2934, 2860, 1773, 1201, 1112 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.67 (d, J=7.6 Hz, 4H), 7.52–7.35 (m, 6H), 4.56 (dd, J=8.4,
3.2 Hz, 1H), 3.87 (dd, J=11.2, 3.2 Hz, 1H), 3.68 (dd, J=11.2, 3.2 Hz,
1H), 2.97–2.73 (m, 1H), 2.59 (ddd, J=12.8, 9.6, 2.8 Hz, 1H), 1.98 (ddd,
J=12.8, 9.6, 9.2 Hz, 1H), 1.30 (d, J=7.2 Hz, 3H), 1.07 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d=180.3, 135.6 (2C), 135.5 (2C), 132.9,
132.5, 129.9 (2C), 127.8 (4C), 77.5, 65.5, 34.2, 32.2, 26.7 (3C), 19.2,
16.4 ppm; HRMS (ESI): m/z: calcd for C22H28O3Si+Na+: 391.1705;
found: 391.1704.
MgBr2·OEt2 (2.98 g, 11.5 mmol) was added at ꢀ788C to a solution of al-
dehyde 28 obtained above in CH2Cl2 (30 mL), and the mixture was
stirred for 45 min. Allyltributyltin (3.8 mL, 12.3 mmol) was introduced
dropwise into the mixture, which was stirred for another 2 h at the same
temperature. Upon completion of the reaction (TLC), it was quenched
with a saturated aqueous solution of NH4Cl (20 mL), and the mixture
was extracted with EtOAc (2ꢂ20 mL). The combined organic layer was
washed with brine (20 mL) and dried with anhydrous Na2SO4. Evapora-
tion of the solvent gave the crude residue, which upon purification by
silica gel column chromatography (petroleum ether/EtOAc=7:3) afford-
ed 29 (0.543 g, 66%) as a colorless oil. ½aꢁ2D4 =ꢀ2.13 (c=0.8, CHCl3); IR
25: MeOH (0.21 mL, 7.25 mmol) and LiBH4 (2.0m in THF, 7.3 mL,
14.51 mmol) were added to a precooled (08C) solution of lactone 24
(2.67 g, 7.25 mmol) in THF (30 mL), and the mixture was stirred at room
temperature for 1 h. Upon completion of the reaction (TLC), it was
quenched with a saturated aqueous solution of NH4Cl (20 mL), and the
mixture was extracted with EtOAc (2ꢂ30 mL). The combined organic
extract was dried with anhydrous Na2SO4, and the residue thus obtained
after evaporation of the solvent was purified by silica gel column chroma-
tography (petroleum ether/EtOAc=2:3) to afford 25 (2.56 g, 95%) as
a colorless oil. ½aꢁ2D4 = +2.9 (c=1.7, CHCl3); IR (neat): n˜ =3366, 2931,
(neat): n˜ =3480, 2939, 1383, 1220, 1164, 1058 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=5.89 (ddd, J=17.2, 10.4, 3.2 Hz, 1H), 5.18–5.03 (m, 2H), 3.89
(d, J=12.0 Hz, 1H), 3.73 (dd, J=10.8, 6.0 Hz, 1H), 3.48–3.44 (m, 1H),
3.38 (d, J=12.0 Hz, 1H), 2.36 (d, J=4.0 Hz, 1H), 2.31 (dd, J=8.8,
4.0 Hz, 1H), 2.27–2.13 (m, 1H), 1.92–1.80 (m, 1H), 1.69–1.61 (m, 1H),
1.41 (d, J=14.0 Hz, 1H), 1.36 (s, 3H), 1.33 (s, 3H), 1.03 ppm (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=134.7, 117.2, 100.9, 73.3,
70.6, 66.0, 38.2, 37.5, 30.9, 25.4, 24.8, 17.0 ppm; HRMS (ESI): m/z: calcd
for C12H22O3 +Na+: 237.1467; found: 237.1469.
2860, 1462, 1111 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.65 (d, J=
;
7.6 Hz, 4H), 7.51–7.34 (m, 6H), 3.95–3.81 (m, 1H), 3.61 (dd, J=10.0,
3.6 Hz, 1H), 3.58–3.38 (m, 3H), 2.85 (brs, 2H), 1.92–1.77 (m, 1H), 1.51–
1.35 (m, 2H), 1.07 (s, 9H), 0.90 ppm (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=135.50 (2C), 135.49 (2C), 133.1, 133.0, 129.8
(2C), 127.8 (4C), 69.3, 68.0, 67.6, 36.4, 32.3, 26.8 (3C), 19.2, 16.9 ppm;
HRMS (ESI): m/z: calcd for C22H32O3Si+Na+: 395.2018; found:
395.2017.
30: NaH (60% dispersion in mineral oil, 0.30 g, 7.57 mmol) was added at
08C to a solution of alcohol 29 (0.81 g, 3.78 mmol) in dry DMF (15 mL),
and the mixture was stirred at the same temperature for 1 h. p-Methoxy-
benzyl chloride (1.0 mL, 7.57 mmol) was then introduced into the mix-
ture, which was stirred at room temperature for another 1 h. Upon com-
pletion of the reaction (TLC), it was quenched with water (10 mL), and
the mixture was extracted with diethyl ether (3ꢂ20 mL). The combined
organic extract was stirred with silica gel (2.0 g) for 0.5 h. Evaporation of
solvent gave the crude residue, which upon purification by silica gel
column chromatography (petroleum ether/EtOAc=1:9) gave 30 (1.06 g,
95%) as a colorless oil. ½aꢁD24 = +33.3 (c=1.0, CHCl3); IR (neat): n˜ =
26: 2,2-Dimethoxypropane (1.9 mL, 15.0 mmol) and camphorsulfonic
acid (0.035 g, 0.15 mmol) were added at 08C to a solution of diol 25
(2.8 g, 7.53 mmol) in CH2Cl2 (15 mL), and the mixture was stirred at
room temperature for 1 h. Upon completion of the reaction (TLC), it
was quenched with a saturated aqueous solution of NaHCO3 (15 mL),
and the mixture was extracted with EtOAc (2ꢂ20 mL). The combined
organic extract was washed with brine (20 mL) and dried with anhydrous
Na2SO4. Evaporation of the solvent followed by silica gel column chro-
matography (petroleum ether/EtOAc=9:1) of the crude residue fur-
nished 26 (2.9 g, 94%) as a colorless oil. ½aꢁ2D4 =ꢀ13.86 (c=1.5, CHCl3);
3410, 2934, 1612, 1514, 1038 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.25
;
Chem. Asian J. 2014, 9, 3431 – 3439
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S. Mothish Kumar, Kavirayani R. Prasad
(d, J=8.8 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.94–5.76 (m, 1H), 5.20–5.03
(m, 2H), 4.63 (d, J=10.8 Hz, 1H), 4.41 (d, J=10.8 Hz, 1H), 3.79 (s, 3H),
3.69 (dd, J=11.6, 6.4 Hz, 1H), 3.54–3.37 (m, 2H), 3.35 (q, J=5.6 Hz,
1H), 2.92 (brs, 2H), 2.55–2.38 (m, 1H), 2.36–2.21 (m, 1H), 1.89 (sext.,
J=6.0 Hz, 1H), 1.58–1.45 (m, 2H), 0.92 ppm (d, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=159.3, 133.9, 130.1, 129.5 (2C), 117.5,
113.9 (2C), 81.2, 71.9, 69.9, 67.3, 55.2, 36.8, 34.6, 32.3, 17.3 ppm; HRMS
(ESI): m/z: calcd for C17H26O4 +Na+: 317.1729; found: 317.1731.
25.8 (3C), 18.4, 18.3, 18.0, ꢀ4.2, ꢀ4.5, ꢀ5.3, ꢀ5.4 ppm; HRMS (ESI): m/
z: calcd for C30H56O5Si2 +Na+: 575.3564; found: 575.3561.
34: l-(+)-Diisopropyl tartrate (0.02 g, 0.06 mmol), TiACTHUNRGTNEUNG(OiPr)4 (0.02 mL,
0.06 mmol), and tert-butylhydroperoxide (5m in decane, 0.08 mL,
0.4 mmol) were added sequentially at ꢀ238C to a stirred suspension of
powdered 4 ꢃ molecular sieves (0.3 g) in dry CH2Cl2 (2 mL). The mix-
ture was stirred at the same temperature for 45 min, and a solution of
allyl alcohol 33 (0.10 g, 0.18 mmol) in dry CH2Cl2 (2 mL) was added
dropwise; the mixture was stirred for 12 h. Upon completion of the reac-
tion (TLC), it was quenched with H2O (4 mL), and 10% NaOH/saturat-
ed aqueous NaCl solution (1:1, 2.0 mL) was added to the mixture, which
was stirred vigorously at room temperature for 1 h. The mixture was then
filtered through a short pad of Celite, and the Celite pad was washed
with CH2Cl2 (10 mL). The solvent was evaporated off, and the crude resi-
due thus obtained was purified by silica gel column chromatography (pe-
troleum ether/EtOAc=4:1) to afford epoxy alcohol 34 (0.096 g, 94%) as
a colorless oil. ½aꢁ2D4 =ꢀ37.92 (c=2.6, CHCl3); IR (neat): n˜ =3456, 2956,
31: 2,6-Lutidine (2.5 mL, 20.8 mmol) and tert-butyldimethylsilyl triflate
(2.4 mL, 10.4 mmol) were added successively to a precooled (08C) solu-
tion of alcohol 30 (1.02 g, 3.47 mmol) in CH2Cl2 (20 mL), and the mixture
was stirred at room temperature for 1 h. Upon completion of the reaction
(TLC), it was diluted with diethyl ether (20 mL), and the mixture was
washed with a saturated aqueous solution of NaHCO3 (20 mL). The com-
bined organic extract was dried with anhydrous Na2SO4, and the solvent
was evaporated under reduced pressure to give a crude residue, which
upon purification by silica gel column chromatography (petroleum ether/
EtOAc=9:1) furnished 31 (1.74 g, 96%) as a colorless oil. ½aꢁ2D4 =ꢀ21.33
2932, 1464, 1252, 836 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.24 (d, J=
;
(c=1.2, CHCl3); IR (neat): n˜ =2955, 2859, 1613, 1514, 1258 cmꢀ1
;
8.4 Hz, 2H), 6.86 (dd, J=8.4, 2.0 Hz, 2H), 4.56 and 4.46 (ABq, J=
11.2 Hz, 2H), 4.00–3.96 (m, 1H), 3.85 (d, J=12.4 Hz, 1H), 3.79 (s, 3H),
3.63–3.49 (m, 2H), 3.46 (dd, J=9.6, 4.8 Hz, 1H), 3.35 (dd, J=9.6, 6.4 Hz,
1H), 3.04 (ddd, J=6.8, 4.8, 2.0 Hz, 1H), 2.95 (dt, J=4.4, 2.4 Hz, 1H),
1.90–1.85 (m, 3H), 1.85–1.60 (m, 2H), 1.15–1.05 (m, 1H), 0.91 (d, J=
6.4 Hz, 3H), 0.88 (s, 9H), 0.85 (s, 9H), 0.034 (s, 6H), 0.029 (s, 3H),
0.018 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.2, 130.6, 129.3
(2C), 113.8 (2C), 79.0, 71.9, 69.7, 67.7, 61.6, 59.2, 55.2, 54.1, 34.7, 32.1,
31.2, 25.9 (3C), 25.8 (3C), 18.5, 18.3, 17.9, ꢀ4.2, ꢀ4.6, ꢀ5.38, ꢀ5.40 ppm;
HRMS (ESI): m/z: calcd for C30H56O6Si2 +Na+: 591.3513; found:
591.3510.
1H NMR (400 MHz, CDCl3): d=7.24 (d, J=7.6 Hz, 2H), 6.86 (d, J=
8.4 Hz, 2H), 5.89–5.82 (m, 1H), 5.08 (d, J=17.2 Hz, 1H), 5.01 (dd, J=
10.0, 1.2 Hz, 1H), 4.51 and 4.47 (ABq, J=12.4 Hz, 2H), 3.89 (dd, J=8.4,
4.0 Hz, 1H), 3.80 (s, 3H), 3.48 (dd, J=9.6, 4.8 Hz, 1H), 3.43–3.26 (m,
2H), 2.48–2.35 (m, 1H), 2.28–2.10 (m, 1H), 1.22–1.62 (m, 2H), 1.23–1.12
(m, 1H), 0.93 (d, J=6.4 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.044 (s,
3H), 0.040 (s, 3H), 0.03 (s, 3H), 0.0 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=159.1, 136.7, 130.9, 129.2 (2C), 116.1, 113.6 (2C), 81.5, 71.7,
70.5, 67.8, 55.2, 35.0, 33.4, 32.2, 26.0 (3C), 25.9 (3C), 18.4, 18.3, 18.0,
ꢀ4.2, ꢀ4.5, ꢀ5.4 ppm (2C); HRMS (ESI): m/z: calcd for C29H54O4Si2 +
Na+: 545.3458; found: 545.3460.
35: DMSO (1.0 mL), diisopropylethylamine (1.0 mL, 5.80 mmol), and
SO3·Py (0.46 g, 2.9 mmol) were added at 08C to a solution of alcohol 34
(0.33 g, 0.58 mmol) in CH2Cl2 (10 mL), and the mixture was stirred at
room temperature for 1 h. Upon completion of the reaction (indicated by
TLC), the mixture was diluted with water (10 mL) and extracted with
Et2O (2ꢂ10 mL). The combined organic extract was washed with brine
(10 mL) and dried with anhydrous Na2SO4. Evaporation of solvent gave
the crude aldehyde, which was used as such in the next reaction without
further purification.
32: Methyl acrylate (2.4 mL, 26.8 mmol) and Grubbs second-generation
catalyst (57 mg, 0.067 mmol) were added to a solution of olefin 31 (0.7 g,
1.34 mmol) in CH2Cl2 (13 mL), and the mixture was heated at reflux for
2 h. Upon completion of the reaction (TLC), the solvent was evaporated
off, and the crude residue thus obtained was purified by silica gel column
chromatography (petroleum ether/EtOAc=9:1) to afford 32 (0.65 mg,
84%) as a colorless oil. ½aꢁ2D4 =ꢀ23.42 (c=1.2, CHCl3); IR (neat): n˜ =
2955, 2859, 1726, 1254, 836 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.23
;
(d, J=8.8 Hz, 2H), 7.05–6.89 (m, 1H), 6.87 (dd, J=6.8, 2.0 Hz, 2H), 5.86
(d, J=15.6 Hz, 1H), 4.50 and 4.44 (ABq, J=11.6 Hz, 2H), 3.99–3.85 (m,
1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.45 (dd, J=9.6, 4.8 Hz, 1H), 3.42 (dt, J=
7.2, 3.6 Hz, 1H), 3.36 (dd, J=9.6, 6.0 Hz, 1H), 2.56–2.50 (m, 1H), 2.41–
2.25 (m, 1H), 1.85–1.58 (m, 2H), 1.24–1.07 (m, 1H), 0.93 (d, J=6.4 Hz,
3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.05 (s, 3H), 0.049 (s, 3H), 0.04 (s, 3H),
0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=166.9, 159.2, 147.6,
130.4, 129.3 (2C), 122.3, 113.7 (2C), 80.5, 71.8, 70.1, 67.7, 55.2, 51.4, 34.8,
32.1, 32.0, 25.9 (3C), 25.8 (3C), 18.4, 18.3, 17.9, ꢀ4.2, ꢀ4.6, ꢀ5.3,
ꢀ5.4 ppm; HRMS (ESI): m/z: calcd for C31H56O6Si2 +Na+: 603.3513;
found: 603.3516.
Sodium hexamethyldisilazane (2.0m in THF, 1.5 mL, 2.9 mmol) was
added to
+A(PPh)3Brꢀ (1.2 g,
a precooled (08C) solution of CH3P CHTUNTGNRUEGN
3.5 mmol) in THF (4 mL), and the mixture was stirred for 0.5 h. The mix-
ture was then cooled to ꢀ408C, and a solution of the aldehyde obtained
above in THF (4 mL) was added dropwise; the mixture was then stirred
for another 2 h. Upon completion of the reaction (TLC), it was quenched
with H2O (5 mL), and the mixture was extracted with EtOAc (2ꢂ
10 mL). The combined organic layer was washed with brine (10 mL) and
dried with anhydrous Na2SO4. Evaporation of the solvent gave the crude
residue, which upon purification by silica gel column chromatography
(petroleum ether/Et2O=9:1) afforded 35 (0.24 g, 74%) as a colorless oil.
½aꢁ2D4 =ꢀ26.3 (c=1.0, CHCl3); IR (neat): n˜ =3437, 2931, 2858, 1612,
33: DIBAL-H (1.7 mL, 1.7 mmol) was added at ꢀ788C to a solution of
ester 32 (0.49 g, 0.85 mmol) in CH2Cl2 (10 mL), and the mixture was
stirred at the same temperature for 10 min. Upon completion of the reac-
tion (TLC), it was quenched with an aqueous saturated solution of
sodium potassium tartrate (10 mL), and the mixture was stirred at room
temperature for 0.5 h. The mixture was then extracted with EtOAc (2ꢂ
20 mL), and the combined organic extract was washed with brine
(10 mL) and dried with anhydrous Na2SO4. Evaporation of solvent gave
the crude residue, which upon purification by silica gel column chroma-
tography (petroleum ether/EtOAc=4:1) gave 33 (0.43 g, 92%) as a color-
less oil. ½aꢁ2D4 =ꢀ24.12 (c=1.6, CHCl3); IR (neat): n˜ =3443, 2955, 2859,
1083 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.26 (d, J=8.8 Hz, 2H), 6.87
;
(d, J=11.2 Hz, 2H), 5.59 (ddd, J=17.4, 10.0, 7.6 Hz, 1H), 5.45 (d, J=
17.4 Hz, 1H), 5.27 (d, J=10.0 Hz, 1H), 4.56 and 4.49 (ABq, J=11.2 Hz,
2H), 3.94 (dt, J=8.0, 3.6 Hz, 1H), 3.82 (s, 3H), 3.65–3.51 (m, 1H), 3.48
(dd, J=9.6, 4.8 Hz, 1H), 3.37 (dd, J=9.6, 6.4 Hz, 1H), 3.15 (dd, J=7.2,
1.6 Hz, 1H), 3.01–2.88 (m, 1H), 1.90–1.75 (m, 2H), 1.75–1.60 (m, 2H),
1.13 (ddd, J=13.6, 8.8, 5.2 Hz, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.91 (s, 9H),
0.88 (s, 9H), 0.057 (s, 3H), 0.054 (s, 3H), 0.046 (s, 3H), 0.03 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=159.2, 135.9, 130.7 (2C), 129.3, 119.0,
113.7 (2C), 78.9, 71.9, 69.8, 67.7, 59.6, 58.6, 55.3, 34.7, 32.2, 31.7, 25.9
(3C), 25.8 (3C), 18.5, 18.4, 18.0, ꢀ4.2, ꢀ4.6, ꢀ5.36, ꢀ5.38 ppm; HRMS
(ESI): m/z: calcd for C31H56O5Si2 +Na+: 587.3564; found: 587.3565.
1513, 1252, 1080, 836 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.24 (d, J=
;
8.8 Hz, 2H), 6.88 (dd, J=6.4, 2.0 Hz, 2H), 5.74–5.61 (m, 2H), 4.52 and
4.43 (ABq, J=11.6 Hz, 2H), 4.06 (brs, 2H), 3.97–3.83 (m, 1H), 3.81 (s,
3H), 3.49 (dd, J=9.6, 4.8 Hz, 1H), 3.43–3.39 (m, 2H), 2.46–2.32 (m, 1H),
2.26–2.09 (m, 1H), 1.85–1.61 (m, 2H), 1.31–1.19 (m, 2H), 0.94 (d, J=
4.0 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.05 (s, 9H), 0.02 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=159.1, 130.9, 130.8, 130.6, 129.4 (2C),
113.6 (2C), 81.4, 71.6, 70.4, 67.8, 63.8, 55.3, 35.0, 32.2, 31.7, 25.9 (3C),
36: DDQ (0.14 g, 0.6 mmol) was added to a solution of 35 (0.17 g,
0.3 mmol) in CH2Cl2/phosphate buffer pH 7 (19:1, 10 mL), and the result-
ing mixture was stirred at room temperature for 1 h. Upon completion of
the reaction (TLC), it was diluted with a saturated aqueous solution of
NaHCO3 (10 mL), and the mixture was extracted with EtOAc (2ꢂ
20 mL). The combined organic layer was dried with anhydrous Na2SO4,
Chem. Asian J. 2014, 9, 3431 – 3439
3437
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
S. Mothish Kumar, Kavirayani R. Prasad
and the residue obtained after evaporation of the solvent was purified by
silica gel column chromatography (petroleum ether/EtOAc=4:1) to
afford 36 (0.12 g, 89%) as a colorless oil. ½aꢁ2D4 =ꢀ4.9 (c=1.0, CHCl3)
{Ref. [4a] ½aꢁ2D0 =ꢀ26.0 (c=1.0, CHCl3)}; IR (neat): n˜ =3473, 2956, 2859,
ered starting material 37 (0.016 g); further elution gave required alcohol
3 (0.02 g, 50%, 77% based on recovered starting material) as a colorless
oil. ½aꢁ2D4 = +9.4 (c=1.0, CHCl3) {Ref. [2] ½aꢁD20 = +6.7 (c=1.0, CHCl3)};
IR (neat): n˜ =3424, 2932, 2859, 1737, 1459, 1254 cmꢀ1
;
1H NMR
1463, 1255 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.60 (ddd, J=17.2,
;
(400 MHz, CDCl3): d=5.65 (dd, J=15.6, 7.2 Hz, 1H), 5.47 (dt, J=15.6,
6.4 Hz, 1H), 5.35 (dd, J=15.6, 5.2 Hz, 1H), 5.14–5.08 (m, 2H), 4.05–3.92
(m, 2H), 3.81 (dd, J=10.8, 5.2 Hz, 1H), 3.50–3.32 (m, 2H), 2.99 (dd, J=
8.8, 1.2 Hz, 1H), 2.79 (d, J=10.0 Hz, 1H), 2.40 (dd, J=18.0, 5.6 Hz, 1H),
2.36–2.24 (m, 2H), 2.19–2.09 (m, 1H), 2.03–1.97 (m, 1H), 1.95 (dd, J=
18.0, 6.4 Hz, 1H), 1.83–1.75 (m, 2H), 1.58–1.51 (m, 1H), 1.31–1.20 (m,
2H), 0.97 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.88
(s, 9H), 0.87 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.042 (s,
3H), 0.039 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
172.7, 137.2, 132.2, 129.4, 129.1, 77.6 (2C), 71.7, 70.8, 67.8, 59.4, 57.5, 38.1,
37.6, 36.6, 32.7, 32.0, 28.3, 26.0 (3C), 25.9 (3C), 25.7 (3C), 21.2, 18.2,
18.1, 18.0, 17.9, ꢀ4.2 (2C), ꢀ4.3, ꢀ4.4, ꢀ4.5, ꢀ4.6 ppm; HRMS (ESI): m/
z: calcd for C38H74O7Si3 +Na+: 749.4640; found: 749.4642.
10.0, 7.6 Hz, 1H), 5.48 (dd, J=17.2, 1.2 Hz, 1H), 5.28 (d, J=10.0 Hz,
1H), 3.78–3.62 (m, 2H), 3.47 (dd, J=9.6, 5.2 Hz, 1H), 3.38 (dd, J=9.6,
6.4 Hz, 1H), 3.15 (dd, J=7.6, 2.0 Hz, 1H), 3.12–3.00 (m, 1H), 2.29 (d, J=
8.4 Hz, 1H), 1.90 (ddd, J=14.0, 9.6, 4.0 Hz, 1H), 1.81 (ddd, J=14.0, 8.8,
4.4 Hz, 1H), 1.73–1.62 (m, 1H), 1.47 (ddd, J=14.0, 7.6, 3.6 Hz, 1H), 1.19
(ddd, J=14.0, 8.8, 4.4 Hz, 1H), 0.92–0.90 (m, 21H), 0.10 (s, 3H), 0.08 (s,
3H), 0.04 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=135.6, 119.2,
73.2, 69.9, 68.4, 58.8, 58.2, 37.3, 37.2, 32.2, 25.9 (3C), 25.8 (3C), 18.3, 18.0,
17.1, ꢀ4.1, ꢀ4.5, ꢀ5.4 ppm (2C); HRMS (ESI): m/z: calcd for
C23H48O4Si2 +Na+: 467.2989; found: 467.2989.
4: Et3N (0.04 mL, 0.24 mmol) and 2,4,6-trichlorobenzoyl chloride
(0.03 mL, 0.19 mmol) were added at room temperature to a solution of
acid 22 (0.072 g, 0.16 mmol) in benzene (2 mL). After stirring the mixture
for 1 h, a solution of alcohol 36 (0.06 g, 0.135 mmol) and DMAP (0.02 g,
0.135 mmol) in benzene (2 mL) was added to the mixture at room tem-
perature, which was stirred for 4 h. Upon completion of the reaction
(TLC), it was quenched with a saturated solution of NH4Cl (5 mL), and
the mixture was extracted with Et2O (2ꢂ20 mL). The combined organic
extract was washed with brine (10 mL) and dried with anhydrous
Na2SO4. Evaporation of the solvent gave the crude residue, which upon
purification by silica gel column chromatography (petroleum ether) af-
forded 4 (0.098 g, 84%) as a colorless oil. ½aꢁ2D4 =ꢀ36.1 (c=2.4, CHCl3);
Acknowledgements
We thank the Department of Science and Technology (DST), New Delhi
for funding. K.R.P. is a Swarnajayanthi fellow of DST, New Delhi.
S.M.K. thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi for a senior research fellowship.
IR (neat): n˜ =2956, 2932, 2859, 1739, 1076 cmꢀ1 1H NMR (400 MHz,
;
[1] Isolation of iriomoteolide 3a: K. Oguchi, M. Tsuda, R. Iwamoto, Y.
Okamoto, J. Kobayashi, E. Fukushi, J. Kawabata, T. Ozawa, A.
Masuda, Y. Kitaya, K. Omasa, J. Org. Chem. 2008, 73, 1567.
[2] R. Cribiffl, C. Jäger, C. Nevado, Angew. Chem. Int. Ed. 2009, 48,
8780; Angew. Chem. 2009, 121, 8938.
[3] Ch. R. Reddy, G. Dharmapuri, N. N. Rao, Org. Lett. 2009, 11, 5730.
[4] a) Y. Zhang, L. Deng, G. Zhao, Org. Biomol. Chem. 2011, 9, 4518;
for the synthesis of some of the fragments of iriomoteolide 3a, see:
b) C. Y. Chang, J. Chin. Chem. Soc. 2011, 58, 31; c) Ch. R. Reddy, G.
Dharmapuri, Synthesis 2013, 673.
[5] a) K. R. Prasad, O. Revu, J. Org. Chem. 2014, 79, 1461; b) S. K.
Sunnam, K. R. Prasad, Tetrahedron 2014, 70, 2096; c) A. B. Pawar,
K. R. Prasad, Chem. Eur. J. 2012, 18, 15202; d) K. R. Prasad, O.
Revu, Synthesis 2012, 2243; e) K. R. Prasad, P. Gutala, Tetrahedron
2011, 67, 4514; f) K. R. Prasad, A. B. Pawar, Org. Lett. 2011, 13,
4252; g) K. R. Prasad, V. R. Gandi, Tetrahedron: Asymmetry 2011,
22, 499; h) K. R. Prasad, K. Penchalaiah, Tetrahedron 2011, 67,
4268; i) K. R. Prasad, V. R. Gandi, J. E. Nidhiry, K. S. Bhat, Synthe-
sis 2010, 2521.
[6] K. R. Prasad, K. Penchalaiah, J. Org. Chem. 2011, 76, 6889.
[7] a) A. Nakayama, N. Kogure, M. Kitajima, H. Takayama, Org. Lett.
2009, 11, 5554; b) M. J. Wu, J. Y. Yeh, Tetrahedron 1994, 50, 1073.
[8] Stereochemistry of the threo alcohol was assigned by analogy to the
reductions of structurally similar ketones derived from tartrate
amide. For reduction of unsaturated ketones derived from tartaric
acid amide, see: a) K. R. Prasad, S. M. Kumar, Synlett 2011, 1602;
b) P. K. Metri, R. Schiess, K. R. Prasad, Chem. Asian J. 2013, 8, 488.
[9] N. Ikemoto, S. L. Schreiber, J. Am. Chem. Soc. 1992, 114, 2524.
[10] B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981, 37,
2091.
CDCl3): d=5.88 (ddd, J=17.2, 10.4, 4.4 Hz, 1H), 5.59–5.35 (m, 4H), 5.25
(dd, J=10.4, 1.2 Hz, 1H), 5.18 (d, J=17.6 Hz, 1H), 5.10 (d, J=10.4 Hz,
1H), 5.08–4.96 (m, 1H), 4.14–4.01 (m, 2H), 3.91–3.81 (m, 1H), 3.42 (dd,
J=9.6, 5.2 Hz, 1H), 3.32 (dd, J=9.6, 6.0 Hz, 1H), 3.09 (d, J=7.6 Hz,
1H), 2.92–2.80 (m, 1H), 2.34 (dd, J=14.8, 4.8 Hz, 1H), 2.15–1.93 (m,
4H), 2.00–1.83 (m, 1H), 1.82–1.63 (m, 2H), 1.64–1.54 (m, 1H), 0.96–0.84
(m, 43H), 0.13 (s, 3H), 0.09 (s, 3H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s,
3H), 0.03 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=172.5, 137.3,
135.5, 131.3, 129.0, 119.3, 115.1, 76.1, 75.9, 72.7, 70.0, 67.7, 59.1, 57.7, 41.2,
39.5, 35.5, 31.9, 31.6, 30.1, 25.9 (6C), 25.8 (6C), 19.3, 18.3, 18.2, 18.1, 18.0,
17.9, ꢀ4.3, ꢀ4.5, ꢀ4.64, ꢀ4.67, ꢀ4.7, ꢀ4.8, ꢀ5.41, ꢀ5.44 ppm; HRMS
(ESI): m/z: calcd for C46H92O7Si4 +Na+: 891.5818; found: 891.5817.
37: Grubbs second-generation catalyst (2.0 mg, 0.0025 mmol) was added
to a solution of 4 (0.046 g, 0.053 mmol) in toluene (75 mL), and the mix-
ture was stirred at room temperature for 8 h. Upon completion of the re-
action (TLC), the solvent was evaporated off, and the crude residue thus
obtained was purified by silica gel column chromatography (petroleum
ether/EtOAc=9:1) to afford macrolactone 37 (0.029 g, 66%) as a color-
less oil. ½aꢁ2D4 = +5.75 (c=1.2, CHCl3); IR (neat): n˜ =2956, 2859, 1739,
1
1652, 1255, 1076 cmꢀ1; H NMR (400 MHz, CDCl3): d=5.66 (dd, J=15.6,
7.6 Hz, 1H), 5.49 (dt, J=15.6, 6.4 Hz, 1H), 5.38 (dd, J=15.6, 5.2 Hz,
1H), 5.12 (dd, J=15.6, 8.8 Hz, 1H), 5.01 (dd, J=11.6, 2.4 Hz, 1H), 4.08–
3.95 (m, 2H), 3.84 (dt, J=8.4, 4.4 Hz, 1H), 3.39 (d, J=5.2 Hz, 2H), 3.00
(dd, J=8.8, 1.2 Hz, 1H), 2.78 (d, J=10.0 Hz, 1H), 2.45–2.27 (m, 3H),
2.23–2.13 (m, 1H), 1.97 (dd, J=18.0, 6.0 Hz, 1H), 1.91–1.74 (m, 1H),
1.80–1.65 (m, 1H), 1.63–1.47 (m, 1H), 1.35–1.16 (m, 1H), 1.22–1.05 (m,
1H), 0.99 (d, J=6.8 Hz, 3H), 0.93–0.83 (m, 39H), 0.14 (s, 3H), 0.08 (s,
3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H), 0.02 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=172.5, 137.0, 132.2, 129.3, 129.2,
77.7, 77.3, 72.2, 70.1, 67.4, 59.4, 57.7, 38.0, 37.6, 35.2, 31.8, 31.6, 28.1, 25.9
(12C), 21.1, 18.3, 18.2, 18.1, 18.0, 17.9, ꢀ4.2 (2C), ꢀ4.3 (3C), ꢀ4.6, ꢀ5.4,
ꢀ5.5 ppm; HRMS (ESI): m/z: calcd for C44H88O7Si4 +Na+: 863.5505;
found: 863.5510.
[11] a) U. Ravid, R. M. Silverstein, L. R. Smith, Tetrahedron 1978, 34,
1449; b) S. Hanessian, P. J. Murray, Tetrahedron 1987, 43, 5055; c) S.
Hanessian, P. J. Roy, M. Petrini, P. J. Hodges, D. R. Fabio, G. Carga-
nico, J. Org. Chem. 1990, 55, 5766.
3: NH4F (0.02 g, 0.56 mmol) was added to a solution of 37 (0.046 g,
0.055 mmol) in MeOH/THF (10:1, 2 mL), and the mixture was stirred at
room temperature for 48 h. The mixture was then diluted with brine
(5 mL) and extracted with EtOAc (2ꢂ10 mL). The organic layer was
dried with anhydrous Na2SO4, and evaporation of the solvent under re-
duced pressure gave the crude residue, which upon purification by silica
gel column chromatography (petroleum ether/EtOAc=9:1) gave recov-
[12] Ch. R. Reddy, N. N. Rao, Tetrahedron Lett. 2010, 51, 5840.
[13] G. E. Keck, E. P. Boden, Tetrahedron Lett. 1984, 25, 265.
[14] Efforts to isolate the PMB ether of 29 were futile. We observed con-
sistently deprotection of the acetonide group in the silica gel purifi-
cation of the PMB ether of 29. Given that deprotection of the aceto-
nide is the next step, we treated the mixture with silica gel to get
1,4-diol 30 cleanly.
Chem. Asian J. 2014, 9, 3431 – 3439
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
S. Mothish Kumar, Kavirayani R. Prasad
[15] A similar reaction sequence was employed for the conversion of 34
into 36 by Zhang et al. in their synthesis of 2, which is the isopropy-
lidene derivative of iriomoteolide 3a.
[16] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
Received: June 2, 2014
Published online: September 18, 2014
Chem. Asian J. 2014, 9, 3431 – 3439
3439
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim