First stereoselective total synthesis of isoaspinonene through a Baylis-Hillman/olefin cross-metathesis protocol

Article abstract of DOI:10.1002/ejoc.201101211

The first stereoselective and efficient total synthesis of isoaspinonene by using Baylis-Hillman reaction, chelation-controlled vinyl Grignard reaction, Wittig olefination, and olefin cross-metathesis reaction of a hitherto unreported substrate as the key

Full text of DOI:10.1002/ejoc.201101211

FULL PAPER
DOI: 10.1002/ejoc.201101211
First Stereoselective Total Synthesis of Isoaspinonene through a Baylis–
Hillman/Olefin Cross-Metathesis Protocol
Palakodety Radha Krishna,*[a] Munagala Alivelu,[a] and Tadikamalla Prabhakar Rao[b]
Keywords: Allylic compounds / Grignard reaction / Wittig reactions / Baylis–Hillman reaction / Metathesis
The first stereoselective and efficient total synthesis of iso-
aspinonene by using Baylis–Hillman reaction, chelation-con-
trolled vinyl Grignard reaction, Wittig olefination, and olefin
cross-metathesis reaction of a hitherto unreported substrate
as the key steps is described.
Introduction
Isoaspinonene (1) was produced from the cultures of As-
pergillus ochraceus.[1] The other aspinonene and aspyrone
co-metabolites are trienediol; aspinolide A, B, and C; dihy-
droaspyrone; and dienetriol (Figure 1). All the structures
were determined by detailed spectroscopic analysis. Second-
ary metabolites are useful for transferring their chirality to
the desired products. Tetrahydrofuran 1 may be derived bio-
synthetically from intramolecular nucleophilic attack of the
primary hydroxy group on the epoxide in co-metabolite 2
(Scheme 1).
Scheme 1. Proposed biogenetic relationship between 1 and 2.
quitous presence of this core structure in the furano lignan
class of natural products.[3] It was noticed that natural prod-
ucts belonging to this class exhibit “2,3-trans and 3,4-trans”
stereochemistry (e.g., sesaminone, magnolone).[4] Over the
last few years, we have been involved in expanding the syn-
thetic utility of the Baylis–Hillman reaction.[5] The dia-
stereoselective version of this reaction results in products
wherein the newly created chiral center is predominantly
anti to the existing one.[5a] Bearing this in mind, herein we
identified that intermediate 13 (Scheme 2), realized from the
Baylis–Hillman reaction, could be used in the synthesis of
2,3,4-trisubstituted tetrahydrofuran 12, which in turn could
be extrapolated to target molecule isoaspinonene (1). Thus,
the combination of the Baylis–Hillman reaction and an in-
tramolecular tetrahydrofuran ring formation sequence is a
useful strategy in the synthesis of different 2,3,4-trisubsti-
tuted tetrahydrofurans.
Figure 1. Secondary metabolites of Aspergillus ochraceus.
On the basis of synthetic approaches involving olefin
cross-metathesis,[6] we conceived a simple and concise route
to 1. Earlier, we synthesized one of the members of this
family, that is, aspinolide B.[7] In continuation, herein, we
report a convergent approach toward the first total synthe-
sis of 1 starting from inexpensive and commercially avail-
able starting materials: propylene oxide, d-glucose, and (S)-
ethyl lactate. Our synthetic route relies on the Baylis–Hill-
man reaction, chelation-controlled Grignard reaction, Wit-
tig olefination, and olefin cross-metathesis as key transfor-
mation. Accordingly, the envisaged retrosynthetic analysis
for 1 is shown in Scheme 2. The trans-olefinic double bond
of 1 could be constructed by the cross-metathesis of olefin
7 with allylic alcohol 8Јa. Compound 8Јa could be obtained
Tetrahydrofurans are the core unit of many natural prod-
ucts.[2] Construction of optically pure 2,3,4-trisubstituted
tetrahydrofuran derivatives is attractive because of the ubi-
[a] D-211, Discovery Laboratory,
Division of Organic & Biomolecular Chemistry,
Indian Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91-40-27160387
E-mail: prkgenius@iict.res.in
[b] National Center for Magnetic Resonance,
Indian Institute of Chemical Technology,
Hyderabad 500607, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101211.
616
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 616–622

First Stereoselective Total Synthesis of Isoaspinonene
Scheme 3. Reagents and conditions: (a) Ethyl acrylate, DABCO,
DMSO, r.t., 24 h, 85%. (b) MOMCl, DIPEA, CH2Cl2, 0 °C to r.t.,
24 h, 90%. (c) 1. DDQ, CH2Cl2/H2O (9:1), 0 °C to r.t., 1 h, 95%;
2. DIBAL-H, CH2Cl2, 0 °C to r.t., 0.5 h, 93%. (d) TsCl, Et3N,
CH2Cl2, 0 °C to r.t., 24 h, 81%. (e) O3, CH2Cl2, –78 °C, 1 h, 95%.
DABCO = 1,4-diazabicyclo[2.2.2]octane.
Later, the para-methoxybenzyl (PMB) group in 13 was
deprotected upon treatment with DDQ, and the ester group
was reduced to an alcohol with DIBAL-H to produce diol
16 (88% over two steps). Diol 16 was treated with TsCl for
selective tosylation at the primary position. Upon internal
nucleophilic substitution by the secondary hydroxy group
with concomitant elimination of the tosyl group, the tosyl-
ated product gave cyclic ether 12 (81%). Ozonolysis of cy-
clic ether 12 produced ketone 17 and MOM-deprotected
ketone 18 (95% combined yield).
Under these ozonolysis conditions it was observed that
the MOM group was cleaved to afford 18 (15%). Hence,
the MOM group was cleaved prior to ozonolysis by using
TFA and the hydroxy group was reprotected as acetyl ester
19 (90% over two steps) with AcCl, which upon ozonolysis
afforded acetylated ketone 9a in 90% yield (Scheme 4). An
acetyl group was considered as the appropriate protecting
group because it can survive the ozonolysis conditions.
Scheme 2. Retrosynthetic analysis.
by chelation-controlled vinylation of ketone 9a. For ac-
cessing cyclic ketone 9a, we devised two synthetic routes:
the “asymmetric approach” (path A) and the “chiron ap-
proach” (path B). Thus, the late-stage intermediate, meth-
oxymethyl (MOM)-protected cyclic ether 12, could be pre-
pared from Baylis–Hillman adduct 13, which could be real-
ized from chiral aldehyde 14 that could be easily generated
from rac-propylene oxide. Alternatively, ketone 9a could be
realized through path B from alcohol 10 starting from d-
glucose. Thus, alcohol 10 could be obtained from diol 11
by intramolecular etherification. Ketone 9a upon selective
vinylation gives cyclic allyl alcohol 8Јa. The other olefinic
partner, 7, could be prepared from (S)-ethyl lactate by tert-
butyldiphenylsilyl (TBDPS) etherification, reduction of the
ester functionality to the aldehyde, followed by Wittig ole-
fination. Cross-metathesis of 7 and 8Јa and subsequent de-
protection affords target molecule 1.
Scheme 4. Reagents and conditions: (a) 1. TFA, CH2Cl2, 0 °C to
r.t., 1 h; 2. AcCl, Et3N, CH2Cl2, 0 °C to r.t., 1 h, 90% (over two
steps). (b) O3, CH2Cl2, –78 °C, 1 h, 90%.
The chiron approach for the synthesis of 9a is shown in
Scheme 5. Accordingly, the acetonide group of benzoate es-
ter 20[8] was hydrolyzed with 40% aq. acetic acid under re-
Results and Discussion
As shown in Scheme 3, Baylis–Hillman reaction of alde- flux conditions to furnish the corresponding diol, which
hyde 14[7] obtained from propylene oxide through hydro- upon oxidative cleavage with NaIO4 and reduction of the
lytic kinetic resolution (HKR) with ethyl acrylate gave ad- in situ generated aldehyde with NaBH4 gave crucial diol 11
duct 15 (85%) as a mixture of diastereomers (9.4:0.6 ratio (88% over three steps). Selective tosylation of diol 11 by
as determined by HPLC). The secondary hydroxy group in using TsCl resulted in the tosylated product, which upon
adduct 15 was protected with a MOM group by using chlo- intramolecular nucleophilic attack with the oxyanion gener-
romethyl methyl ether (MOMCl) in the presence of N,N- ated with K2CO3 produced cyclic ether 21 (81% over two
diisopropylethylamine (DIPEA) to give 13 (90%).
steps). The secondary alcohol of ether 21 was protected
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617

P. Radha Krishna, M. Alivelu, T. Prabhakar Rao
FULL PAPER
with AcCl as the acetyl ester (85% yield), the benzyl group dition occurred as earlier to afford 8a (Table 1, Entry 2).
was deprotected under hydrogenation conditions, and the Next, 17 was selected as the test substrate, wherein the vinyl
resulting secondary alcohol 10 (90%) under Dess–Martin addition reaction proceeded as in the previous case (i.e., for
periodinane (DMP) oxidation conditions gave ketone 9a 9a) to afford 17a in high selectivity. Subsequently, to prove
(92%).
that the addition reaction favored anti-products, 8Јa and
17a were subjected to respective deprotection reactions to
afford the respective diols 8b, which were then compared. It
was found that the diols obtained from 8Јa and 17a shared
comparable data. This chemical correlation method proves
the anti-addition of two variable substrates. Interestingly, 8a
was identified as starting material 10 and bears identical
data. Thus, this set of reactions established that the ring
oxygen atom plays the crucial role and that the countercat-
ion doe not play a role in the addition reaction. It also
proves the relative anti-stereochemistry of the C3 and C4
carbon atoms of the addition products unequivocally.
Scheme 5. Reagents and conditions: (a) See ref.[8] (b) 1. 40%
AcOH, H2SO4, reflux, 1 h; 2. NaIO4, MeOH/H2O (9:1), r.t., 0.5 h;
3. NaBH4, MeOH, 0 °C to r.t., 10 min (88% over three steps).
(c) 1. TsCl, Et3N, CH2Cl2, 0 °C to r.t., 24 h; 2. K2CO3, MeOH, r.t.,
0.5 h, 81% (over two steps). (d) 1. AcCl, Et3N, CH2Cl2, 0 °C to r.t.,
0.5 h, 85%; 2. Pd/C, H2, EtOAc, r.t., 3 h, 90%. (e) DMP, CH2Cl2,
0 °C to r.t., 1 h, 92%.
Table 1. Examples for stereoselective additions to ketones.
Entry Ketone
Reagent
Solvent Yield
[%]
t
t
[h]
dr
[°C]
1
2
3
9a
9a
17
vinylMgBr
NaBH4
vinylMgBr
THF
MeOH
THF
93
95
90
–78
0
–78
1
0.25
1
9:1[a]
9.1:0.9[b]
9.5:0.5[a]
Ketone 9a upon chelation-controlled vinylation
(Scheme 6) with vinylMgBr furnished crucial tertiary allylic
alcohol 8Јa (93%) with 9:1dr (as determined by H NMR
[a] Determined by 1H NMR spectroscopy. [b] Determined by
HPLC.
1
spectroscopy) in favor of the required isomer. Herein, unlike
the conventional cyclic alkoxy ketones,[9] substrate 9a is en-
Thus the absolute stereochemistry at C4 was assigned as
dowed with a more nucleophilic ring oxygen atom, which (R) from the above experiments. Allylic alcohol 8Јa consti-
participates in the formation of a five-membered chelation tutes an important fragment of the cross-metathesis reac-
complex involving the ketone and the magnesium to facili- tion. Next, we accessed olefinic partner 7 (Scheme 7). Ac-
tate the anti-addition and to result in compound 8Јa in high cordingly, upon reduction with DIBAL-H at –78 °C,
selectivity.
TBDPS-protected (S)-ethyl lactate gave the aldehyde, which
upon Wittig olefination gave olefin 7 (61% over two steps).
Scheme 7. Reagents and conditions: (a) TBDPSCl, imidazole,
CH2Cl2, 0 °C to r.t., 3 h, 96%. (b) 1. DIBAL-H, CH2Cl2, –78 °C,
1 h; 2. Ph3P=CH2, THF, –5 °C to r.t., 6 h, 61% (over two steps).
Our next aim was to construct the main skeleton of tar-
get 1 by coupling olefinic partners 7 and 8Јa by using the
olefin cross-metathesis protocol (Scheme 8). To the best of
our knowledge, although cross-metathesis of tertiary allylic
alcohols has been reported,[11a–11c] the use of cyclic tertiary
allylic alcohols such as 8Јa is rare, except for a few related
cyclic substrates.[11d] Initially, we attempted the reaction in
CH2Cl2 and toluene as the solvents. However, the best re-
sult was obtained when the olefin cross-metathesis was per-
formed with 7 and 8Јa in a 2:1 ratio in toluene at 110 °C
Scheme 6. Reagents and conditions: (a) NaBH4, MeOH, 0 °C,
15 min, 95%; (b) vinylMgBr, THF, –78 °C, 1 h, 93 and 90%;
(c) K2CO3, MeOH, r.t., 0.5 h, 90%; (d) TFA, CH2Cl2, 0 °C to r.t.,
1 h, 85%.
To validate the hypothesis that the ring oxygen atom is (Table 2, Entry 4). All the results are presented in Table 2.
involved in the complexation during the addition reaction As outlined in Scheme 8, the crucial olefin cross-metathesis
and that it is this oxygen atom that dictates the stereochemi- reaction with the use of Hoveyda–Grubbs II[12] catalyst (A,
cal outcome of the reaction and not the oxygen atom of the 10 mol-%/toluene/110 °C) between 7 and 8Јa (2:1) resulted
3-acetoxy, 3-hydroxy, or 3-MOM ether group, we con- in cross-product 22 (60%) as a single stereoisomer with (E)
ducted[10] additional experiments, and the results are listed configuration (determined by 1H NMR spectroscopy) in
in Table 1. For instance, when 9a was subjected to the hy- which the olefinic protons resonated at δ = 5.82 ppm with
dride addition (wherein the countercation is Na+), the ad- J = 15.2 Hz and at δ = 5.47 ppm with J = 15.6 Hz indicat-
618
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Eur. J. Org. Chem. 2012, 616–622

First Stereoselective Total Synthesis of Isoaspinonene
60–120 mesh). 1H NMR (200, 300, 400, and 500 MHz) and 13C
NMR (75 MHz) spectra were measured with a Varian Gemini FT-
200 MHz, Bruker Avance 300 MHz, Unity 400 MHz, or Inova-
500 MHz spectrometer with tetramethylsilane as the internal stan-
dard. IR spectra were recorded with a Perkin–Elmer IR-683 spec-
trophotometer with NaCl optics. Optical rotations were measured
with a JASCO DIP 300 digital polarimeter at 25 °C. Mass spectra
were recorded with a Fannigan Mat 1210 double focusing mass
spectrometer operating at a direct inlet system.
ing the trans geometry of the olefinic protons and that a
small amount of homodimer 23 (5%) was also formed. It
is pertinent to mention that Grubbs I and II catalysts either
failed to initiate the coupling reaction or gave low yields of
the expected product. Now, all that remained was to hy-
drolyze the acetyl ester and to deprotect the TBDPS group.
Thus, cross-product 22 was hydrolyzed in the presence of
K2CO3 to produce 24 (94%), and deprotection of the silyl
ether with TBAF gave target 1 (80%).
Ethyl
2-{(1S,2R)-1-Hydroxy-2-[(4-methoxybenzyl)oxy]propyl}-
stirred solution of aldehyde 14 (1.0 g,
acrylate (15): To
a
5.15 mmol) in DMSO (5 mL) was added ethyl acrylate (0.56 mL,
15.45 mmol) and DABCO (1.73 g, 5.15 mmol). After stirring for
24 h, the reaction mixture was extracted with diethyl ether
(3ϫ10 mL). The combined organic layer was washed with water
(2ϫ10 mL) and brine (2ϫ10 mL), dried (Na2SO4), and concen-
trated. The residue was purified by column chromatography (silica
gel 60–120 mesh; EtOAc/n-hexane, 1.5:8.5) to furnish Baylis–Hill-
man adduct 15 (1.28 g, 85%) as a colorless oily liquid. [α]2D5 = –14.2
1
(c = 0.75, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.22 (d, J =
8.3 Hz, 2 H, Ar-H), 6.82 (d, J = 8.3 Hz, 2 H, Ar-H), 6.29 (s, 1 H,
C=CH2), 5.96 (s, 1 H, C=CH2), 4.64 (br. s, 1 H, OCH), 4.50 (d, J
= 1.8 Hz, 2 H, OCH2), 4.35 (d, J = 11.3 Hz, 1 H, OCH), 4.16 (m,
2 H, OCH2CH3), 3.78 (s, 3 H, OCH3), 1.28 (t, J = 6.7 Hz, 3 H,
CH2-CH3), 1.02 (d, J = 6.4 Hz, 3 H, CH-CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.9, 158.6, 140.5, 139.0, 129.2, 126.3,
113.6, 76.5, 75.4, 71.6, 70.3, 60.5, 13.9, 13.2 ppm. IR (neat): ν =
˜
3480, 2981, 1712, 1513, 1301, 1248, 1175, 1088, 820 cm–1. MS
(ESI): m/z = 317 [M + Na]+. C16H22O5 (294.35): calcd. C 65.29, H
7.53; found C 65.30, H 7.55. HPLC (Atlantis dC18, 150ϫ 4.6 mm,
5 U, mobile phase = 55% CH3CN + 45% H2O, flow rate =1 mL/
min, DAD): tR = 4.905 (major), 4.406 (minor) min.
Scheme 8. Reagents and conditions: (a) Hoveyda–Grubbs II (A,
10 mol-%), toluene, 110 °C, 1 h, 60%; (b) K2CO3, MeOH, 0.5 h,
94%; (c) TBAF, THF, 0 °C to r.t., 12 h, 80%.
Ethyl 2-[(1S,2R)-2-[(4-Methoxybenzyl)oxy]-1-(methoxymethoxy)-
propyl]acrylate (13): To a stirred solution of alcohol 15 (1.25 g,
4.25 mmol) in CH2Cl2 (10 mL) was added DIPEA (2.74 mL,
21.25 mmol) and MOMCl (0.68 mL, 8.5 mmol). After stirring for
24 h, the reaction mixture was washed with water (2ϫ5 mL) and
brine (2ϫ5 mL), dried (Na2SO4), and concentrated. The residue
was purified by column chromatography (EtOAc/n-hexane, 1.0:9.0)
Table 2. Study of the olefin cross-metathesis reaction of 7 and 8Јa
with catalyst A (10 mol-%) under various conditions.
Entry
7/8Јa
[equiv.]
Solvent
Temp.
[°C]
Time
[h]
Yield[a] [%]
22/23
to furnish 13 (1.29 g, 90%) as a light yellow oily liquid. [α]2D5
=
1
2
3
4
1:2
1:2
2:1
2:1
CH2Cl2
toluene
CH2Cl2
toluene
40
110
40
20
1
20
1
60:10
60:10
60:5
+11.0 (c = 0.9, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 7.23 (d,
J = 7.8 Hz, 2 H, Ar-H), 6.80 (d, J = 8.0 Hz, 2 H, Ar-H), 6.32 (s, 1
H, C=CH2), 5.89 (s, 1 H, C=CH2), 4.85–4.45 (m, 6 H, 6 OCH),
4.17 (dd, J = 5.2, 9.0 Hz, 2 H), 3.78 (s, 3 H, OCH3), 3.37 (s, 3 H,
OCH3), 1.28 (t, J = 7.7 Hz, 3 H, CH2-CH3), 1.11 (d, J = 6.5 Hz, 3
H, OCH-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.0, 158.3,
141.4, 130.6, 128.8, 126.2, 113.4, 95.1, 76.1, 75.3, 70.4, 60.6, 55.6,
110
60:5
[a] Isolated yields after purification by column chromatography.
55.1, 14.2, 14.0 ppm. IR (neat): ν = 3020, 2982, 2135, 1728, 1322,
˜
Conclusions
1158, 1035, 758, 665 cm–1. MS (ESI): m/z = 361 [M + Na]+.
C18H26O6 (338.40): calcd. C 63.89, H 7.74; found C 63.90, H 7.75.
In summary, the first stereoselective synthesis of iso-
aspinonene (1) was achieved by Baylis–Hillman reaction
and a cross-metathesis strategy, which was used to access
(3S,4R)-3-Methoxymethoxy-2-methylenepentane-1,4-diol (16): To a
stirred solution of 13 (1.25 g, 3.69 mmol) in CH2Cl2/H2O (9:1,
advanced intermediate 22 that was endowed with all stereo- 15 mL) was added DDQ (1.00 g, 4.43 mmol) at 0 °C, and the mix-
ture was stirred for 1 h. A saturated NaHCO3 solution was added,
and the mixture was extracted with CH2Cl2 (2ϫ10 mL). The com-
bined organic layer was washed with water (2ϫ5 mL) and brine
(2ϫ5 mL), dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (EtOAc/n-hexane, 2:8) to yield
the alcohol (0.76 g, 95%). To a stirred solution of this alcohol
(0.75 g, 3.44 mmol) in CH2Cl2 (7 mL) was added DIBAL-H
(5.85 mL, 4.12 mmol) at 0 °C, and the solution was stirred for
0.5 h. The reaction mixture was quenched with saturated Na/K tar-
genic centers and was easily transformed into target com-
pound 1.
Experimental Section
General Methods: Organic solutions were dried with anhydrous
Na2SO4 and concentrated below 40 °C in vacuo. All column chro-
matographic separations were performed by using silica gel (Acme
Eur. J. Org. Chem. 2012, 616–622
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P. Radha Krishna, M. Alivelu, T. Prabhakar Rao
FULL PAPER
tarate solution, filtered through filter paper, and washed with
CH2Cl2 (20 mL). The combined organic layer was concentrated,
and the residue was purified by column chromatography (EtOAc/
combined organic layer was concentrated in vacuo to afford the
aldehyde as a colorless liquid. To a stirred solution of this aldehyde
(1.5 g, 4.57 mmol) in MeOH (20 mL) was added NaBH4 (0.086 g,
n-hexane, 3.0:7.0) to furnish diol 16 (0.56 g, 93%) as a colorless 2.28 mmol) at 0 °C, and the reaction mixture was stirred for
syrup. [α]2D5 = +32.6 (c = 0.3, CHCl3). 1H NMR (200 MHz, CDCl3):
δ = 5.39 (d, J = 0.7 Hz, 1 H, C=CH2), 5.17 (d, J = 0.7 Hz, 1 H,
10 min. After completion of the reaction, the mixture was diluted
with MeOH and concentrated in vacuo. The crude residue was
C=CH2), 4.61 (d, J = 6.6 Hz, 1 H, OCH), 4.52 (d, J = 6.6 Hz, 1 purified by column chromatography (EtOAc/n-hexane, 2.0:8.0) to
H, OCH), 4.15 (d, J = 12.4 Hz, 1 H, OCH), 4.01–3.91 (m, 3 H, 3 afford diol 11 (1.43 g, 88% over three steps) as a syrupy liquid.
OCH), 3.36 (s, 3 H, OCH3), 1.19 (d, J = 5.8 Hz, 3 H, OCH- [α]2D5 = –102.9 (c = 2.5, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 119.7, 110.1, 94.1,
7.99 (d, J = 7.1 Hz, 2 H, Ar-H), 7.53 (t, J = 7.1 Hz, 1 H, Ar-H),
7.40 (t, J = 7.5 Hz, 2 H, Ar-H), 7.29–7.15 (m, 5 H, Ar-H), 5.16 (p,
J = 6.4 Hz, 1 H, OCH), 4.66–4.48 (m, 2 H, 2 OCH), 3.87–3.69 (m,
3 H, 3 OCH), 3.61–3.57 (m, 1 H, OCH), 1.43 (d, J = 6.0 Hz, 3 H,
OCH-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.5, 137.4,
132.9, 130.2, 129.6, 128.4, 128.3, 128.2, 127.9, 76.6, 74.2, 72.8, 70.8,
82.8, 68.8, 62.5, 55.8, 18.7 ppm. IR (neat): ν = 3118, 2926, 1400,
˜
1261, 1089, 1028, 757 cm–1. C8H16O4 (176.21): calcd. C 54.53, H
9.15; found C 54.50, H 9.17.
(2R,3S)-3-Methoxymethoxy-2-methyl-4-methylenetetrahydrofuran
(12): To a stirred solution of diol 16 (0.50 g, 2.84 mmol) in CH2Cl2
(15 mL) was added Et3N (0.81 mL, 5.68 mmol) and TsCl (0.49 g,
2.55 mmol) at 0 °C. After stirring for 24 h to room temperature,
the solvent was evaporated and the residue was purified by column
chromatography (EtOAc/n-hexane, 0.5:9.5) to furnish 12 (0.36 g,
62.0, 16.7 ppm. IR (neat): ν = 3440, 2965, 2885, 1750, 1520, 1250,
˜
1020, 770, 830 cm–1. MS (ESI): m/z = 331 [M + H]+, 353
[M + Na]+. C19H22O5 (330.38): calcd. C 69.07, H 6.71; found C
69.09, H 6.69.
81%) as a colorless oil. [α]2D5 = +23.0 (c = 0.25, CHCl3). H NMR
1
(2R,3S,4R)-4-Benzyloxy-2-methyltetrahydro-3-furanyl Acetate (21):
To a stirred solution of diol 11 (1.40 g, 4.24 mmol) in CH2Cl2
(20 mL) was added Et3N (1.17 mL, 8.48 mmol) and TsCl (0.80 g,
4.24 mmol) at 0 °C. After stirring for 24 h to room temperature,
the solvent was removed, and the residue was purified by column
chromatography (EtOAc/n-hexane, 0.4:9.6) to furnish the tosyl es-
ter (1.84 g, 90%), which was used as such in the next step. To a
stirred solution of the tosyl ester (1.80 g, 3.71 mmol) in MeOH
(20 mL) was added K2CO3 (1.52 g, 11.13 mmol), and the mixture
was stirred for 0.5 h. The reaction mixture was filtered through
filter paper and washed with EtOAc (20 mL). The combined or-
ganic layer was concentrated, and the residue was purified by col-
umn chromatography (EtOAc/n-hexane, 0.5:9.5) to furnish cyclic
alcohol 21 (0.69 g, 90%) as a colorless oil. [α]2D5 = –42.1 (c = 0.5,
(300 MHz, CHCl3): δ = 5.55 (s, 1 H, C=CH2), 5.35 (s, 1 H,
C=CH2), 4.65 (d, J = 6.4 Hz, 1 H, OCH), 4.56 (d, J = 6.8 Hz, 1
H, OCH), 4.20–4.01 (m, 3 H, 3 OCH), 4.00–3.87 (m, 1 H, OCH),
3.40 (s, 3 H, OCH3), 1.20 (d, J = 6.4 Hz, 3 H, OCH-CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 142.1, 120.0, 94.7, 82.2, 68.5,
55.8, 44.3, 18.6 ppm. IR (neat): ν = 3118, 2926, 1400, 1261, 1089,
˜
1028, 757 cm–1. C8H14O3 (158.20): calcd. C 60.74, H 8.92; found C
60.72, H 8.95.
(2R,3R)-2-Methyl-4-oxotetrahydro-3-furanyl Acetate (9a): To
a
solution of 12 (0.2 g, 1.28 mmol) in CH2Cl2 (2 mL) was added TFA
(0.1 mL) at 0 °C, and the solution was stirred to room temperature
for 1 h. The excess amount of TFA was removed under vacuum,
the reaction mixture was concentrated, and the residue was used
for acetylation. To a solution of this residue in CH2Cl2 (2 mL) was
added Et3N (0.45 mL, 3.2 mmol) and AcCl (0.15 mL, 1.06 mmol)
at 0 °C. After stirring to room temperature for 1 h, the reaction
mixture was concentrated, and the residue was purified by column
chromatography (EtOAc/n-hexane, 0.5:9.5) to afford ester 19
(0.176 g, 90% over two steps) as a colorless liquid. To a stirred
solution of ester 19 (0.08 g, 0.51 mmol) in CH2Cl2 (5 mL) was
passed O3 for 1 h at –78 °C. The reaction mixture was quenched
with DMS, washed with water (2ϫ2 mL) and brine (2ϫ2 mL),
dried (Na2SO4), and concentrated. The residue was purified by col-
umn chromatography (EtOAc/n-hexane, 0.3:9.7) to furnish 9a
(0.072 g, 90%) as yellow oily liquid. [α]2D5 = –104.23 (c = 0.5,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.32–7.22 (m, 5 H, Ar-
H), 4.53 (s, 2 H, OCH2), 3.95–3.90 (m, 2 H, OCH2), 3.89–3.81 (m,
2 H, 2 OCH), 3.70 (p, J = 5.9 Hz, 1 H, OCH), 1.29 (d, J = 6.43 Hz,
3 H, OCH-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.0,
128.5, 127.8, 127.7, 85.9, 82.0, 80.8, 71.6, 70.7, 18.4 ppm. IR (neat):
ν = 3435, 2965, 2885, 1520, 1270, 1025, 775, 820 cm–1. MS (ESI):
˜
m/z = 231 [M + Na]+. C12H16O3 (208.26): calcd. C 69.21, H 7.74;
found C 69.18, H 7.76.
(2R,3S,4R)-4-Hydroxy-2-methyltetrahydro-3-furanyl Acetate (10):
To a stirred solution of alcohol 21 (0.65 g, 3.12 mmol) in CH2Cl2
(10 mL) was added Et3N (1.3 mL, 9.36 mmol) and AcCl (0.22 mL,
3.12 mmol) at 0 °C. After stirring for 1 h at room temperature, the
reaction mixture was washed with water (2ϫ5 mL) and brine
(2ϫ5 mL), dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (EtOAc/n-hexane, 0.2:9.8) to
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 4.87 (d, J = 8.6 Hz, 1
H, OCH), 4.18 (d, J = 17.3 Hz, 1 H, OCH), 4.09–3.94 (m, 2 H, 2
OCH), 2.16 (s, 3 H, COCH3), 1.46 (d, J = 6.0 Hz, 3 H, OCH-
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.3, 169.5, 77.6,
furnish acetyl ester (0.66 g, 85%) as a colorless oily liquid. [α]2D5
=
1
+27.03 (c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.29–
7.22 (m, 5 H, Ar-H), 4.87 (d, J = 2.2 Hz, 1 H, OCH), 4.63 (d, J =
12.0 Hz, 1 H, OCH), 4.52 (d, J = 12.0 Hz, 1 H, OCH), 4.03–3.82
(m, 4 H, 4 OCH), 2.06 (s, 3 H, COCH3), 1.35 (d, J = 6.4 Hz, 3 H,
OCH-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.1, 137.7,
128.4, 127.9, 127.7, 83.2, 82.2, 80.0, 71.5, 71.2, 21.0, 18.8 ppm. To
a stirred solution of this acetyl ester (0.60 g, 2.6 mmol) in EtOAc
(7.0 mL) was added Pd/C (catalytic) at room temperature, and the
75.5, 70.4, 20.4, 18.4 ppm. IR (neat): ν = 3445, 2985, 2880, 1740,
˜
1680, 1520, 1275, 1020, 705 cm–1. C7H10O4 (158.15): calcd. C 53.16,
H 6.37; found C 53.19, H 6.35.
(1R,2S,3R)-3-Benzyloxy-2,4-dihydroxy-1-methylbutyl
Benzoate
(11): To stirred solution of benzoyl ester 19 (2.0 g, 5.0 mmol) in
40% aq. acetic acid (10 mL/g) was added H2SO4 (1 mL), and reac-
tion mixture was stirred under reflux for about 1 h. The reaction
mixture was extracted with EtOAc (2ϫ20 mL), dried (Na2SO4), mixture was stirred for 3 h under hydrogen pressure (1 atm) at the
and concentrated to afford the hemiacetal. To a stirred solution of
this hemiacetal (1.7 g, 4.74 mmol) in MeOH/H2O (9:1, 20 mL) was
added NaIO4 (2.03 g, 9.48 mmol) at room temperature, and the
reaction mixture was stirred for 0.5 h. The reaction mixture was
filtered through filter paper and washed with EtOAc (20 mL). The
same temperature. The reaction mixture was filtered through filter
paper and washed with EtOAc (10 mL). The combined organic
layer was evaporated, and the residue was purified by column
chromatography (EtOAc/n-hexane, 1.0:9.0) to furnish alcohol 10
(0.37 g, 90%) as a colorless syrup. [α]2D5 = +90.87 (c = 0.4, CHCl3).
620
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 616–622

First Stereoselective Total Synthesis of Isoaspinonene
1H NMR (300 MHz, CDCl3): δ = 4.42 (dd, J = 5.2, 1.8 Hz, 1 H,
as syrupy liquid. HPLC (Shim-pack XR-ODS-II, 2.0 mm
OCH), 4.18 (p, J = 2.2 Hz, 1 H, OCH), 3.99–3.79 (m, 3 H, 3 OCH), i.d.ϫ75 mm, mobile phase = 70% CH3CN + 30% H2O, flow rate
2.10 (s, 3 H, COCH3), 1.37 (d, J = 6.4 Hz, 3 H, OCH-CH3) ppm.
= 0.2 mL/min, PDA), tR = 1.297 (major), 1.649 (minor) min. The
1H and 13C NMR spectroscopic data were identical to those of
compound 10.
13C NMR (75 MHz, CDCl3): δ = 171.6, 86.6, 79.0, 76.9, 73.0, 20.8,
18.7 ppm. IR (neat): ν = 3425, 2985, 2890, 1750, 1520, 1255, 1020,
˜
780, 815 cm–1. C7H12O4 (160.17): calcd. C 52.49, H 7.55; found C
52.51, H 7.57.
tert-Butyl {[(1S)-1-Methyl-2-propenyl]oxy}diphenylsilane (7): To a
stirred solution of TBDPS-protected ethyl lactate (1.40 g,
3.93 mmol) in dry CH2Cl2 (20 mL) was added DIBAL-H (5.55 mL,
4.71 mmol) at –78 °C, and the mixture was stirred at the same tem-
perature for 1 h. The reaction mixture was quenched with saturated
aq. Na/K tartarate solution, diluted with water (10 mL), and ex-
tracted with dichloromethane (2ϫ10 mL). The combined organic
layer was washed with brine (2ϫ5 mL), dried (Na2SO4), and con-
centrated to give the aldehyde. To a solution of (methyl)triphenyl-
phosphonium iodide (4.43 g, 10.98 mmol) in dry THF (20 mL) was
added KOtBu (1.03 g, 9.15 mmol) at –5 °C, and the mixture was
stirred for 3 h at the same temperature. A solution of the above
aldehyde (1.15 g, 3.66 mmol) in THF (5 mL) was added dropwise,
and the mixture was stirred for 3 h to room temperature. Saturated
aq. NH4Cl (5 mL) was added, and the mixture was extracted with
EtOAc (2ϫ10 mL). The combined organic layer was washed with
water (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated.
The obtained residue was purified by column chromatography
(2R,3R)-2-Methyl-4-oxotetrahydro-3-furanyl Acetate (9a). Path B:
To a stirred solution of alcohol 10 (0.35 g, 2.16 mmol) in anhydrous
CH2Cl2 (7 mL) was added DMP (1.11 g, 2.62 mmol) at 0 °C, and
the mixture was stirred for 1 h at room temperature. The reaction
mixture was washed with water (2ϫ5 mL) and brine (2ϫ5 mL),
dried (Na2SO4), and concentrated. The residue was purified by col-
umn chromatography (EtOAc/n-hexane, 0.2:9.8) to furnish cyclic
ketone 9a (0.31 g, 92%) as a yellow oily liquid. The 1H and 13C
NMR spectroscopic data were identical to those of compound 9a
generated by the asymmetric approach.
(2R,3R,4R)-4-Hydroxy-2-methyl-4-vinyltetrahydro-3-furanyl Acet-
ate (8Јa): To a stirred solution of cyclic ketone 9a (0.1 g, 0.64 mmol)
in anhydrous THF (5 mL) was added vinylMgBr (2.5 mL,
2.56 mmol) at –78 °C, and the mixture was stirred for 1 h at the
same temperature. The reaction mixture was treated with NH4Cl
and washed with EtOAc (2ϫ10 mL). The combined organic layer
was washed with water (2ϫ5 mL) and brine (2ϫ5 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography (EtOAc/n-hexane, 0.5:9.5) to furnish cyclic allylic
alcohol 8Јa (0.11 g, 93%) as a colorless liquid. [α]2D5 = +115.09 (c
= 0.35, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.92 (dd, J =
17.1, 10.5 Hz, 1 H, CH=CH2), 5.39 (d, J = 17.1 Hz, 1 H,
CH=CH2), 5.22 (d, J = 10.5 Hz, 1 H, CH=CH2), 4.70 (d, J =
7.1 Hz, 1 H, OCH), 4.03 (p, J = 6.4 Hz, 1 H, OCH), 3.89 (d, J =
9.6 Hz, 1 H, OCH), 3.72 (d, J = 9.6 Hz, 1 H, OCH), 2.12 (s, 3 H,
COCH3), 1.30 (d, J = 6.2 Hz, 2.7 H, OCH-CH3), 1.24 (d, J =
6.6 Hz, 0.3 H, OCH-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.5, 138.7, 115.2, 96.1, 81.4, 76.9, 75.9, 20.7, 18.6 ppm. IR (neat):
(EtOAc/n-hexane, 0.3:9.7) to furnish olefin 7 (0.74 g, 61%). [α]2D5
=
–5.26 (c = 0.25, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.64 (t,
J = 7.7 Hz, 4 H, Ar-H), 7.39–7.29 (m, 6 H, Ar-H), 5.91–5.75 (m,
1 H, CH=CH2), 5.07 (d, J = 16.9 Hz, 1 H, CH=CH2), 4.92 (d, J
= 10.3 Hz, 1 H, CH=CH2), 4.26 (p, J = 6.0 Hz, 1 H, OCH), 1.11
(d, J = 6.2 Hz, 3 H, OCH-CH3), 1.06 (s, 9 H, 3 C-CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 142.4, 135.8, 129.4, 127.4, 127.3,
112.6, 70.3, 26.9, 24.0, 19.2 ppm. IR (neat): ν = 3430, 2985, 2885,
˜
1720, 1680, 1520, 1265, 1035, 815, 715 cm–1. MS (ESI): m/z = 333
[M + Na]+. C20H26OSi (310.51): calcd. C 77.36, H 8.44; found C
77.38, H 8.45.
(2R,3R,4R)-4-(E,3S)-3-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-1-
butenyl-4-hydroxy-2-methyltetrahydro-3-furanyl Acetate (22) and
(2R,3R,4R)-4-{(E)-2-[(3R,4R,5R)-4-(Acetyloxy)-3-hydroxy-5-
methyltetrahydro-3-furanyl]-1-ethenyl}-4-hydroxy-2-methyltetra-
hydro-3-furanyl Acetate (23): To a stirred solution of cyclic allyl
alcohol 8Јa (0.1 g, 0.53 mmol) in anhydrous toluene (1 mL) was
added olefin 7 (0.33 g, 1.06 mmol) and catalyst A (0.04 g, 10 mol-
%). After stirring at reflux for about 1 h under a nitrogen atmo-
sphere, the solvent was evaporated and the residue was directly ad-
sorbed on silica to perform the column chromatography (EtOAc/
n-hexane, 0.5:9.5) to afford cross-metathesis product 22 (0.14 g,
60%) as a colorless syrupy liquid and 23 (0.09 g, 5%) as a semi-
solid. Data for 22: [α]2D5 = –42.3 (c = 0.15, CHCl3). 1H NMR
(300 MHz, CHCl3): δ = 7.61 (t, J = 4.72 Hz, 4 H, Ar-H), 7.43–7.30
(m, 6 H, Ar-H), 5.82 (dd, J = 15.2, 6.04 Hz, 1 H, CH=CH), 5.47
(d, J = 15.6 Hz, 1 H, CH=CH), 4.59 (d, J = 6.61 Hz, 1 H, OCH),
4.29 (p, J = 6.04 Hz, 1 H, OCH), 3.95 (dt, J = 6.6, 0.5 Hz, 1 H,
OCH), 3.66 (2 d, AB pattern, J = 11.1 Hz, 2 H, OCH2), 2.05 (s, 3
H, COCH3), 1.25 (s, 9 H, 3 C-CH3), 1.09 (br. s, 6 H, 2 CH-
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.2, 135.8, 135.4,
130.8, 129.6, 128.7, 127.4, 81.4, 78.5, 75.9, 69.5, 61.9, 29.7, 29.3,
ν = 3423, 3084, 2927, 1740, 1643, 1375, 1235, 1064, 923 cm–1.
˜
C9H14O4 (186.21): calcd. C 58.05, H 7.58; found C 58.03, H 7.61.
(3R,4R,5R)-Tetrahydro-4-(methoxymethoxy)-5-methyl-3-vinylfuran-
3-ol (17a): To a stirred solution of cyclic ketone 17 (0.1 g,
0.62 mmol) in anhydrous THF (3 mL) was added vinylMgBr
(2.4 mL, 2.41 mmol) at –78 °C, and the mixture was stirred for 1 h
at the same temperature. The reaction mixture was treated with
NH4Cl and washed with EtOAc (2ϫ5 mL). The combined organic
layer was washed with water (2ϫ5 mL) and brine (2ϫ5 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography (EtOAc/n-hexane, 0.6:9.4) to furnish cyclic allylic
alcohol 17a (0.10 g, 90%) as
a
colorless liquid. 1H NMR
(300 MHz, CDCl3): δ = 6.10–5.89 (m, 1 H, CH=CH2), 5.58–5.40
(m, 1 H, CH=CH2), 5.27 (t, J = 10.5 Hz, 1 H, CH=CH2), 4.64 (q,
J = 6.4 Hz, 2 H, OCH2), 4.36 (d, J = 16.6 Hz, 1 H, OCH), 4.25 (d,
J = 16.6 Hz, 1 H, OCH), 4.10–3.95 (m, 2 H, OCH2), 3.33 (s, 2.85
H, OCH3), 3.31 (s, 0.15 H, OCH3), 1.13 (d, J = 6.04 Hz, 3 H,
CHCH ) ppm. IR (neat): ν = 3123, 2927, 1640, 1375, 1064,
˜
3
923 cm–1. C9H16O4 (188.22): calcd. C 57.43, H 8.57; found C 57.39,
H 8.61.
26.9, 22.8, 14.0 ppm. IR (neat): ν = 3425, 2980, 2895, 1725, 1685,
˜
(2R,3S,4R)-4-Hydroxy-2-methyltetrahydro-3-furanyl Acetate (8a): 1530, 1260, 1033, 820, 720 cm–1. MS (ESI): m/z = 491 [M + Na]+.
To a stirred solution of cyclic ketone 9a (0.1 g, 0.64 mmol) in HRMS: calcd. for C27H36O5NaSi 491.2229; found 491.2219. Data
MeOH (2 mL) was added NaBH4 (0.012 g, 0.31 mmol) at 0 °C, and for 23: [α]2D5 = +48.5 (c = 0.2, CHCl3). 1H NMR (500 MHz,
the reaction mixture was stirred for 15 min. After completion of
the reaction, the mixture was diluted with MeOH and concentrated
in vacuo. The crude residue was purified by column chromatog-
raphy (EtOAc/n-hexane, 2.0:8.0) to afford alcohol 8a (0.96 g, 95%)
CHCl3): δ = 5.86 (s, 2 H, 2 CH=CH), 4.69 (d, J = 7.2 Hz, 2 H, 2
OCH), 4.04 (p, J = 6.01 Hz, 2 H, 2 OCH), 3.91 (d, J = 9.6 Hz, 2
H, 2 OCH), 3.77 (d, J = 9.6 Hz, 2 H, 2 OCH), 2.11 (s, 6 H, 2
COCH3), 1.26 (d, J = 3.61 Hz, 6 H, 2 OCH-CH3) ppm. 13C NMR
Eur. J. Org. Chem. 2012, 616–622
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
621

P. Radha Krishna, M. Alivelu, T. Prabhakar Rao
FULL PAPER
(75 MHz, CDCl3): δ = 185.8, 131.2, 81.4, 79.2, 76.3, 75.9, 29.7,
18.4 ppm. MS (ESI): m/z = 377 [M + Na]+. C16H24O8 (344.36):
calcd. C 55.81, H 7.02; found C 55.83, H 7.05.
[1]
[2]
J. Fuchser, A. Zeeck, Liebigs Ann. Recl. 1997, 87–95.
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ida, M. Y. Huang, R. X. Chen, J. R. Liu, M. Nakayama, J.
Antibiot. 1994, 47, 487–491.
a) P. Radha Krishna, R. Sachwani, P. S. Reddy, Synlett 2008,
2897–2912; b) P. Radha Krishna, M. Narasingam, V. Kannan,
Tetrahedron Lett. 2004, 45, 4773–4775; c) P. Radha Krishna,
M. Narsingam, J. Comb. Chem. 2007, 9, 62–69; d) P.
Radha Krishna, P. S. Reddy, J. Comb. Chem. 2008, 10, 426–
435.
(2R,3R,4R)-4-(E,3S)-3-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-1-
butenyl-2-methyltetrahydro-3,4-furandiol (24): To a stirred solution
of 22 (0.12 g, 0.26 mmol) in MeOH (2 mL) was added K2CO3
(0.19 g, 0.78 mmol) at room temperature, and the mixture was
stirred for 0.5 h at the same temperature. The reaction mixture was
filtered through filter paper and washed with EtOAc (5 mL). The
combined organic layer was concentrated, and the residue was puri-
fied by column chromatography (EtOAc/n-hexane, 1.0:9.0) to fur-
nish 24 (0.10 g, 94%) as a colorless syrup. [α]2D5 = –41.3 (c = 0.25,
[3]
[4]
1
CHCl3). H NMR (300 MHz, CHCl3): δ = 7.71–7.58 (m, 4 H, Ar-
H), 7.48–7.30 (m, 6 H, Ar-H), 5.75 (dd, J = 15.1, 6.6 Hz, 1 H,
CH=CH), 5.24 (d, J = 15.4 Hz, 1 H, CH=CH), 4.35 (t, J = 5.85 Hz,
1 H, OCH), 3.75–3.57 (m, 3 H, 3 OCH), 3.13 (d, J = 7.1 Hz, 1 H,
OCH), 1.25 (s, 9 H, 3 C-CH3), 1.09 (br. s, 6 H, 2 CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 135.9, 135.8, 135.1, 129.6, 127.5,
127.4, 81.6, 78.4, 77.7, 77.2, 69.9, 29.6, 26.8, 24.4, 18.4 ppm. IR
[5]
(neat): ν = 3455, 2927, 2856, 1743, 1462, 1371, 1232, 1106,
˜
704 cm–1. MS (ESI): m/z = 449 [M + Na]+. HRMS: calcd. for
[6]
a) P. Radha Krishna, G. Dayaker, Tetrahedron Lett. 2007, 48,
7279–7282; b) P. Radha Krishna, E. Shiva Kumar, Tetrahedron
Lett. 2009, 50, 6676–6679; c) P. Radha Krishna, B. Karu-
nakar Reddy, Tetrahedron Lett. 2010, 51, 6262–6264.
C25H34O4NaSi 449.2124; found 449.2125.
Isoaspinonene (1): To a stirred solution of 24 (0.1 g, 0.23 mmol) in
anhydrous THF (1 mL) was added TBAF (0.2 mL) at 0 °C, and
the mixture was stirred for 12 h. Then, the solvent was evaporated,
and the residue was purified by column chromatography (EtOAc/
n-hexane, 4.0:6.0) to furnish 1 (0.035 g, 80%) as a colorless oil.
[7] P. Radha Krishna, M. Narsingam, Synthesis 2007, 3627–3634.
[8] M. K. Gurjar, T. R. Devi, K. L. N. Reddy, P. A. Sharma,
T. G. M. Dhar, Indian J. Chem., Sect. B 1993, 32B, 995–1003.
[9] K. Maruoka, M. Oishi, K. Shiohara, H. Yamamoto, Tetrahe-
dron 1994, 50, 8983–8996.
1
[α]2D5 = +7.6 (c = 0.15, MeOH). H NMR (500 MHz, CD3OD): δ
[10] The authors are thankful to the referees for suggesting to con-
duct additional experiments to prove that the ring oxygen atom
is involved in the complexation and not the oxygen atom of
the substituent during the ketone addition reaction. This point
was proved by considering substrate 17, wherein the neigh-
boring substituent contains an ether group, but yet the results
reflected the same pattern.
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462; b) A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H.
Grubbs, J. Am. Chem. Soc. 2003, 125, 11360–11370; c) I. C.
Stewart, C. J. Douglas, R. H. Grubbs, Org. Lett. 2008, 10, 441–
444; d) M. Mizutani, F. Inagaki, T. Nakanishi, C. Yanagihara,
I. Tamai, C. Mukai, Org. Lett. 2011, 13, 1796–1799.
[12] a) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
Am. Chem. Soc. 2000, 122, 8168–8179; b) P. Radha Krishna,
R. R. Kadiyala, Tetrahedron Lett. 2010, 51, 2586–2588; c) P.
Radha Krishna, R. R. Kadiyala, Tetrahedron Lett. 2010, 51,
4981–4983.
= 5.89 (dd, J = 15.6, 5.8 Hz, 1 H, CH=CH), 5.68 (d, J = 15.5 Hz,
1 H, CH=CH), 4.27 (p, J = 6.2 Hz, 1 H, OCH), 3.89 (d, J = 9.6 Hz,
1 H, OCH), 3.86 (dq, J = 8.0, 6.1 Hz, 1 H, OCH), 3.71 (d, J =
9.6 Hz, 1 H, OCH), 3.48 (d, J = 8.0 Hz, 1 H, OCH), 1.27 (d, J =
6.2 Hz, 3 H, OCH-CH3), 1.23 (d, J = 6.5 Hz, 3 H, OCH-CH3) ppm.
13C NMR (75 MHz, CD3OD): δ = 135.9, 131.7, 82.9, 79.8, 79.1,
77.7, 68.8, 23.7, 18.8 ppm. IR (neat): ν = 3402, 2967, 2929, 2852,
˜
1065, 975, 941 cm–1. MS (ESI): m/z = 211 [M + Na]+. HRMS:
calcd. for C9H16O4Na 211.0946; found 211.0941.
Supporting Information (see footnote on the first page of this arti-
cle): Selected NMR spectra.
Acknowledgments
M.A. thanks the Council of Scientific and Industrial Research
(CSIR) (New Delhi) for financial support in the form of a fellow-
ship.
Received: August 18, 2011
Published Online: November 30, 2011
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Eur. J. Org. Chem. 2012, 616–622